World Health Organization Classification of Tumours

WHO OMS

International Agency for Research on Cancer (IARC)

Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs

Edited by

John N. Eble Guido Sauter Jonathan I. Epstein Isabell A. Sesterhenn

IARCPress Lyon, 2004

World Health Organization Classification of Tumours
Series Editors Paul Kleihues, M.D. Leslie H. Sobin, M.D.

Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs
Editors John N. Eble, M.D. Guido Sauter, M.D. Jonathan I. Epstein, M.D. Isabell A. Sesterhenn, M.D. Figen Soylemezoglu, M.D. Wojciech Biernat, M.D. Stéphane Sivadier Lauren A. Hunter Allison L. Blum Lindsay S. Goldman Thomas Odin Team Rush 69603 Villeurbanne, France IARCPress International Agency for Research on Cancer (IARC) 69008 Lyon, France

Coordinating Editors

Editorial Assistant Layout

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This volume was produced in collaboration with the

International Academy of Pathology (IAP)

The WHO Classification of Tumours of the Urinary System and Male Genital Organs presented in this book reflects the views of a Working Group that convened for an Editorial and Consensus Conference in Lyon, France, December 14-18, 2002.

Members of the Working Group are indicated in the List of Contributors on page 299.

The WHO Working Group on Tumours of the Urinary System and Male Genital Organs pays tribute to Dr F. Kash Mostofi (1911-2003), outstanding pathologist, who through his vision, teachings and personality influenced generations of physicians worldwide.

Published by IARC Press, International Agency for Research on Cancer, 150 cours Albert Thomas, F-69008 Lyon, France

© International Agency for Research on Cancer, 2004, reprinted 2006 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce figures or charts from this publication should be directed to the respective contributor (see section Source of Charts and Photographs). The designations used and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication. Enquiries should be addressed to the Communications Unit, International Agency for Research on Cancer, 69008 Lyon, France, which will provide the latest information on any changes made to the text and plans for new editions.

Format for bibliographic citations: Eble J.N., Sauter G., Epstein J.I., Sesterhenn I.A. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004

IARC Library Cataloguing in Publication Data Pathology and genetics of tumours of the urinary system and male genital organs / editors J.N. Eble… [et al.] (World Health Organization classification of tumours ; 6) 1. Bladder neoplasms - genetics 2. Bladder neoplasms - pathology 3. Genital neoplasms, male - genetics 4. Genital neoplasms, male - pathology 5. Kidney neoplasms - genetics 6. Kidney neoplasms - pathology 7. Prostatic neoplasms – genetics 8. Prostatic neoplasms - pathology I. Eble, John N. II. Series ISBN 92 832 2412 4 (NLM Classification: WJ 160)

Contents

1 Tumours of the kidney
WHO and TNM classifications Renal cell carcinoma Familial renal cancer Clear cell renal cell carcinoma Multilocular cystic renal cell Papillary renal cell carcinoma Chromophobe renal cell carcinoma Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma Renal carcinomas associated with Xp11.2 translocations / TFE3 gene fusions Renal cell carcinoma associated with neuroblastoma Mucinous tubular spindle cell carcinoma Papillary adenoma of the kidney Oncocytoma Renal cell carcinoma unclassified Metanephric tumours Metanephric adenoma Metanephric adenofibroma Metanephric adenosarcoma Metanephric stromal tumour Nephroblastic tumours Nephroblastoma Nephrogenic rests and nephroblastomatosis Cystic, partially differentiated nephroblastoma Soft tissue tumours Clear cell sarcoma Rhabdoid tumour Congenital mesoblastic nephroma Ossifying renal tumour of infancy Haemangiopericytoma Leiomyosarcoma Osteosarcoma Renal angiosarcoma Malignant fibrous histiocytoma Angiomyolipoma Epithelioid angiomyolipoma Leiomyoma Haemangioma Lymphangioma Juxtaglomerular cell tumour Renomedullary interstitial cell tumour Intrarenal schwannoma Solitary fibrous tumour Cystic nephroma Mixed epithelial and stromal tumour Synovial sarcoma Neural / neuroendocrine tumours Renal carcinoid tumour Neuroendocrine carcinoma

9
10 12 15 23 26 27 30 33 35 37 39 40 41 42 43 44 44 44 46 48 53 55 56 58 60 62 62 63 63 64 64 65 68 70 71 71 72 74 75 75 76 77 79 81 82

Primitive neuroectodermal tumour (Ewing sarcoma) Neuroblastoma Paraganglioma / Phaeochromocytoma Lymphomas Plasmacytoma Leukaemia Germ cell tumours

83 84 85 85 86 87 87

2 Tumours of the urinary system
WHO and TNM classifications Infiltrating urothelial carcinoma Non-invasive urothelial tumours Urothelial hyperplasia Urothelial dysplasia Urothelial papilloma Inverted papilloma Papillary urothelial neoplasm of low malignant potential Non-invasive high grade papillary urothelial carcinoma Urothelial carcinoma in situ Genetics and predictive factors Squamous neoplasms Squamous cell carcinoma Verrucous squamous cell carcinoma Squamous cell papilloma Glandular neoplasms Adenocarcinoma Urachal carcinoma Clear cell adenocarcinoma Villous adenoma Neuroendocrine tumours Small cell carcinoma Paraganglioma Carcinoid Soft tissue tumours Rhabdomyosarcoma Leiomyosarcoma Angiosarcoma Osteosarcoma Malignant fibrous histiocytoma Leiomyoma Other mesenchymal tumours Granular cell tumour Neurofibroma Haemangioma Malignant melanoma Lymphomas Metastatic tumours and secondary extension Tumours of the renal pelvis and ureter Tumours of the urethra

89
90 93 110 111 111 113 114 115 117 119 120 124 127 127 128 131 133 134 135 136 138 139 140 141 142 143 144 144 145 145 146 146 147 148 150 154

3 Tumours of the prostate
WHO and TNM classifications Acinar adenocarcinoma Prostatic intraepithelial neoplasia Ductal adenocarcinoma Urothelial carcinoma Squamous neoplasms Basal cell carcinoma Neuroendocrine tumours Mesenchymal tumours Haematolymphoid tumours Secondary tumours involving the prostate Miscellaneous tumours Tumours of the seminal vesicles

159
160 162 193 199 202 205 206 207 209 212 212 213 214

5 Tumours of the penis
WHO and TNM classifications Malignant epithelial tumours Squamous cell carcinoma Basaloid carcinoma Warty (condylomatous) carcinoma Verrucous carcinoma Papillary carcinoma (NOS) Sarcomatoid (spindle cell) carcinoma Mixed carcinomas Adenosquamous carcinoma Merkel cell carcinoma Small cell carcinoma of neuroendocrine type Sebaceous carcinoma Clear cell carcinoma Basal cell carcinoma Precursor lesions Intraepithelial neoplasia Grade III Giant condyloma Bowen disease Erythroplasia of Queyrat Paget disease Melanocytic lesions Mesenchymal tumours Lymphomas Secondary tumours

279
280 281 283 285 285 286 286 286 287 287 287 287 287 287 287 288 288 288 289 289 290 291 292 297 298

4 Tumours of the testis and paratesticular tissue
WHO and TNM classifications Introduction Germ cell tumours Precursor lesions Seminoma Spermatocytic seminoma Spermatocytic seminoma with sarcoma Embryonal carcinoma Yolk sac tumour Choriocarcinoma Teratomas Dermoid cyst Mixed germ cell tumours Sex cord / gonadal stromal tumours Leydig cell tumour Malignant Leydig cell tumour Sertoli cell tumour Malignant Sertoli cell tumour Granulosa cell tumours Thecoma/fibroma tumours Incompletely differentiated tumours Mixed forms Malignant sex cord / gonadal stromal tumours Tumours containing both germ cell and sex cord / gonadal stromal elements Gonadoblastoma Miscellaneous tumours Lymphoma and plasmacytoma and paratesticular tissues Tumours of collecting ducts and rete Tumours of paratesticular structures Adenomatoid tumour Mesothelioma Adenocarcinoma of the epididymis Papillary cystadenoma of epididymis Melanotic neuroectodermal tumour Desmoplastic small round cell tumour Mesenchymal tumours Secondary tumours

217
218 220 221 228 230 233 235 236 237 240 243 244 246 250 250 251 252 255 255 257 257 257 258 259 259 261 263 265 267 267 267 270 270 271 272 273 277

Contributors Source of charts and photographs References Subject index

299 304 306 353

CHAPTER 1
Tumours of the Kidney

Cancer of the kidney amounts to 2% of the total human cancer burden, with approximately 190,000 new cases diagnosed each year. They occur in all world regions, with a preference for developed countries. Etiological factors include environmental carcinogens (tobacco smoking) and lifestyle factors, in particular obesity. Although renal tumours can be completely removed surgically, haematogeneous metastasis is frequent and may occur already at an early stage of the disease. The pattern of somatic mutations in kidney tumours has been extensively investigated and has become, in addition to histopathology, a major criterion for classification. Kidney tumours also occur in the setting of several inherited cancer syndromes, including von Hippel-Lindau disease.

/3 for malignant tumours. 10 Tumours of the kidney .org).WHO histological classification of tumours of the kidney Renal cell tumours Clear cell renal cell carcinoma Multilocular clear cell renal cell carcinoma Papillary renal cell carcinoma Chromophobe renal cell carcinoma Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma Xp11 translocation carcinomas Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma Renal cell carcinoma. unclassified Papillary adenoma Oncocytoma Metanephric tumours Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumour Nephroblastic tumours Nephrogenic rests Nephroblastoma Cystic partially differentiated nephroblastoma Mesenchymal tumours Occurring Mainly in Children Clear cell sarcoma Rhabdoid tumour Congenital mesoblastic nephroma Ossifying renal tumour of infants Occurring Mainly in Adults Leiomyosarcoma (including renal vein) Angiosarcoma Rhabdomyosarcoma Malignant fibrous histiocytoma 8310/31 8310/3 8260/3 8317/3 8319/3 8319/3 Haemangiopericytoma Osteosarcoma Angiomyolipoma Epithelioid angiomyolipoma Leiomyoma Haemangioma Lymphangioma Juxtaglomerular cell tumour Renomedullary interstitial cell tumour Schwannoma Solitary fibrous tumour Mixed mesenchymal and epithelial tumours Cystic nephroma Mixed epithelial and stromal tumour Synovial sarcoma Neuroendocrine tumours Carcinoid Neuroendocrine carcinoma Primitive neuroectodermal tumour Neuroblastoma Phaeochromocytoma Haematopoietic and lymphoid tumours Lymphoma Leukaemia Plasmacytoma Germ cell tumours Teratoma Choriocarcinoma Metastatic tumours 9150/1 9180/3 8860/0 8890/0 9120/0 9170/0 8361/0 8966/0 9560/0 8815/0 8312/3 8260/0 8290/0 8959/0 9040/3 8325/0 9013/0 8935/1 8960/3 8959/1 8240/3 8246/3 9364/3 9500/3 8700/0 9044/3 8963/3 8960/1 8967/0 9731/3 9080/1 9100/3 8890/3 9120/3 8900/3 8830/3 __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {808} and the Systematized Nomenclature of Medicine (http://snomed. Behaviour is coded /0 for benign tumours. and /1 for borderline or uncertain behaviour.

TNM classification of renal cell carcinoma TNM classification 1. limited to the kidney Tumour 4 cm or less Tumour more than 4 cm but not more than 7 cm Tumour more than 7 cm in greatest dimension. T2. 2 A help desk for specific questions about the TNM classification is available at http://www.2 T – Primary Tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 T1a T1b T2 T3 T3a T3b T3c T4 Tumour 7 cm or less in greatest dimension.uicc.2662}.org/tnm T1 T2 T3 T1. limited to the kidney Tumour extends into major veins or directly invades adrenal gland or perinephric tissues but not beyond Gerota fascia Tumour directly invades adrenal gland or perinephric tissuesa but not beyond Gerota fascia Tumour grossly extends into renal vein(s)b or vena cava or its wall below diaphragm Tumour grossly extends into vena cava or its wall above diaphragm Tumour directly invades beyond Gerota fascia a N – Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single regional lymph node N2 Metastasis in more than one regional lymph node M – Distant Metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping Stage I Stage II Stage III Stage IV Notes: Includes renal sinus (peripelvic) fat b Includes segmental (muscle-containing) branches __________ 1 {944. N1 N2 Any N M0 M0 M0 M0 M0 M0 M1 11 . T3 T4 Any T Any T N0 N0 N0 N1 N0.

1. conducted in many different populations have established that the risk of kidney cancer increases steadily with increasing body mass index (BMI). which thereafter began to slow down or even fall in some high risk countries {2843}.01 Estimates of the age-standardized incidence rates of kidney cancer. From Globocan 2000 {749}. Overall it is the 12th most common site in men and 17th in women. Togashi P. Exposure to carcinogenic arsenic com- pounds in industrial processes or through drinking water increases the risk of renal cancer by 30% {1150}. These trends were paralleled by mortality. The highest rates in both men and women were observed in the Czech Republic with 20 and 10 annual new cases per 100. it is as common as nonHodgkin lymphoma ranking 6th. while in less developed areas it ranks 16th. In women it ranks 12th and 17th in developed and developing countries respectively {749}. Several epidemiological studies both prospective and retrospective. the incidence of renal cell cancer increases steadily after age 40 years as most epithelial tumours but the risk levels off or even declines from age 75 in both sexes. but to date an excess has not been reported in exposed humans. Eble K. These include asbestos.1154}.N. The same authors estimated that in Europe Males Females Fig. Epidemiology of renal cell cancer Renal cell cancer (RCC) represents on average over 90% of all malignancies of the kidney that occur in adults in both sexes. pesticides and fungal toxins. up until the mid-80s {481}. in the same order of magnitude as carcinoma of the nasopharynx. After the low peak in children due to nephroblastoma. Some steroidal estrogens and the nonsteroidal diethylstilboestrol induce tumours in hamster {1150. The incidence of RCC in obese people (BMI>29 kg/m2) is double that of normal individuals and about 50% increased if overweight (BMI 25-30 kg/m2) {221}. The incidence is low in the African and Asian continents but not in Latin America where around 1995 Uruguay recorded one of the highest rates in the world.Renal cell carcinoma J. It is two to three times more common in men than in women in both high and low risk countries {2016}. Etiology Tobacco smoking is a major cause of kidney cancer and accounts for at least 39% of all cases in males {2015}. adjusted to the world standard age distribution (ASR). In males living in industrialized areas including Japan. The latest systematic analyses of time trends of the incidence of kidney cancer indicate a general increase in both sexes in all monitored regions. Several other environmental chemicals have been addressed as possible carcinogens for the kidney but definitive evidence has not been established.000 population respectively. some organic solvents. 12 Tumours of the kidney . Estrogens could be involved in the mechanism that induces RCC in overweight and obese individuals. cadmium. The lowest rates recorded were less that 1 new case per 100. age standardized {2016}. the most common measure of overweight {1156}.000 showing a 10-fold variation in the risk of the disease. Pisani Definition Renal cell carcinoma is a group of malignancies arising from the epithelium of the renal tubules.

Renal cell carcinoma may induce paraneoplastic endocrine syndromes {1441. Normocytic anaemia unrelated to haematuria occurs in about 33% {438. elevation of serum alkaline phosphatase. often with elevated renin concentrations in the renal vein of the tumour-bearing Renal cell carcinoma Fig. transaminase. A real association would be supported by estrogen-mediated carcinogenesis that is documented in animal models. Approximately 33% are hypertensive.03 Age-standardized incidence rates of renal cell cancer recorded by population-based cancer registries around 1995. Parity is a factor that has been investigated in several studies but results are discordant {1430}. Few studies have investigated the hypothesis that genetic characteristics may modulate the effect of exposure to chemical carcinogens.M.2525}.2526}. The association with the use of diuretics instead is referable to hypertension. birth weight {221}. RCC was not associated with the glutatione S-transferase (GST) Fig. anorexia. pain. Conversely. hypertension.02 Age-specific incidence rates of renal cell cancer in selected countries. From D. and flank mass are the classic triad of presenting symptoms. The significance of these associations remain however unclear.one quarter of kidney cancers in both sexes are attributable to excess weight. and alpha-2globulin concentrations may occur in the absence of liver metastases and may resolve when the renal tumour is resected {1441}. but less than 4% have erythrocytosis {902. In about 66% of patients. while a small but consistent excess of RCC has been established with exposure to phenacetin-containing analgesics that also cause cancer of the renal pelvis {1150}. and fever {870}. 1. Parkin et al. erythropoietin concentration is elevated {2526}. it could be a confounded effect of excess body weight that is often increased in women who had many children. Hepatosplenomegaly. 13 . coagulopathy.2912}. including humoral hypercalcemia of malignancy (pseudohyperparathyroidism). low consumption of fruits and vegetables {2841} and the use of antihypertensive drugs other than diuretics. Elevation of the erythrocyte sedimentation rate occurs in approximately 50% of cases {634}. but nearly 40% of patients lack all of these and present with systemic symptoms. but was significantly decreased in either smokers and non-smokers having the GST T1 null genotype {2544}. {2016}. Hypercalcemia without bone metastases occurs in approximately 10% of patients and in nearly 20% of patients with disseminated carcinoma {736}. The incidence of RCC is significantly increased in people with a history of blood hypertension that is independent of obesity and tobacco smoking {458. erythrocytosis. M1 null genotype that is also involved in the metabolism of several carcinogens. abdominal pain. including weight loss. Conversely.962. Systemic amyloidosis of the AA type occurs in about 3% of patients {2705}. In one study the effect of tobacco smoking was stronger in subjects with slow acetylator genotypes as defined by polymorphisms in the N-acetyltransferase 2 gene that is involved in the metabolism of polycyclic aromatic hydrocarbons {2359}. and gynecomastia. Clinical features Signs and symptoms Haematuria. Other exposures that have been addressed are a family history of kidney cancer {829}.902}. 1. The association has been reported as stronger in women than in men in some but not all studies.

but those with enhancement require followups at 6 months. Renal cell carcinoma also is known for presenting as metastatic carcinoma of unknown primary. Lesions without enhancement require nothing further. CT before and after IV contrast is required. and then yearly {258}. 1 year. Increased use of nephron-sparing and laparoscopic surgery underscores the importance of preoperative imaging work-up. sometimes in unusual sites.2491}. Routine staging work-up for renal cell carcinoma includes dynamic CT and chest radiography.kidney {902. 14 Tumours of the kidney . Ultrasonography is useful for detecting renal lesions and if it is not diagnostic of a simple cyst. Gynecomastia may result from gonadotropin {904} or prolactin production {2486}. Imaging The current imaging technology has altered the management of renal masses as it enables detection and characterization of very small masses. Plain CT may confirm a benign diagnosis by identifying fat in angiomyolipoma {284}. Radiological criteria established by Bosniak assist management of renal masses {283}.

Herva L.H. Approximately 25% of haemangioblastomas are associated with VHL disease {1883}. Zbar G. papillary RCC. The syndrome is caused by germline mutations of the VHL tumour suppressor gene.P. regular screening of mutation carriers for renal and extrarenal manifestations is considered mandatory.P. Merino D.Familial renal cell carcinoma M. Synonyms and historical annotation Lindau {1506} described capillary haemangioblastoma.P. epididymal and broad ligament cystadenomas - VHL pVHL Hereditary papillary renal cancer c-MET HGF-R 7q31 Multiple. phaeochromocytoma. pancreatic cysts and neuroendocrine tumours. Incidence Von Hippel-Lindau disease is estimated Table 1. adenomatous polyps of the duodenum and the small intestine. subungual fibromas Cardiac rhabdomyomas. Von Hippel-Lindau disease (VHL) Definition The von Hippel-Lindau (VHL) disease is inherited through an autosomal dominant trait and characterized by the development of capillary haemangioblastomas of the central nervous system and retina. For most of them. phaeochromocytoma. conventional RCC. Eccles W. from C.A. The VHL protein is involved in cell cycle regulation and angiogenesis.2 Facial fibrofolliculomas Tuberous sclerosis TSC1 Hamartin TSC2 Tuberin 9q34 16p13 Multiple. renal cysts Skin Other tissues Retinal and CNS haemangioblastomas. cortical tubers and subependymal giant cell astrocytomas (SEGA) - Constitutional chromosome 3 translocation Unknown Multiple. the oncogene / tumour suppressor gene involved and the respective germline mutations have been identified. pancreatic and inner ear tumours. Algaba B. Launonen R. Linehan F. and to identify asymptomatic gene carriers by germline mutation testing {2510}. Usually. making it possible to confirm the clinical diagnosis syndrome. multiple renal tumours. {2032} Syndrome von Hippel-Lindau Gene Protein Chromosome 3p25 Kidney Multiple. Kovacs P. Modified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. bilateral angiomyolipomas. bilateral papillary renal cell carcinomas (PRCC) Type 1 Papillary renal cell carcinoma (PRCC). Geurts van Kessel M. located on chromosome 3p25–26. 193300 {1679}. Kiuru V. including kidney. lung and kidney cysts. Neumann C. non-Type 1 Multiple chromophobe RCC. clear cell renal carcinoma. bilateral clear-cell renal cell carcinomas (CCRCC) - Familial renal cell carcinoma 15 .M. and tumours of the visceral organs. previously described by von Hippel {2752}. MIM No. Cutaneous angiofibroma lymphangioleiomyomatosis (‘adenoma sebaceum’) peau chagrin. Kleihues A. Pavlovich The kidney is affected in a variety of inherited cancer syndromes.J. and also noted its association with retinal vascular tumours. Aaltonen H. endolymphatic sac tumours of the inner ear. spontaneous pneumothorax 17p11. hybrid oncocytoma. bilateral clear-cell renal cell carcinoma (CCRCC). Pavlovich et al. oncocytic tumours - Hereditary leiomyomatosis and RCC Birt-Hogg-Dubé FH FH BHD Folliculin 1q42-43 Nodules (leiomyomas) Uterine leiomyomas and leiomyosarcomas Lung cysts.M.01 Major inherited tumour syndromes involving the kidney. affected patients develop bilateral.

The mean age of manifestation is 37 years versus 61 years for sporadic CCRCC. Fig. They are typically multifocal and bilateral. bilateral cystic renal lesions. The large tumour has the characteristic yellow appearance of clear cell renal cell carcinoma. including Purkinje cells of the cerebellum {1559. germline VHL mutations can virtually always be identified {2510}. CT scan of a patient with von Hippel-Lindau disease with multiple. The VHL tumour suppressor gene has three exons and a coding sequence of 639 nucleotides {1445}. in particular epithelial cells of the skin. 1. B Higher magnification of a typical clear cell RCC. 25 years) and thus offer the possibility of an early diagnosis. they are predominantly located in the cerebellum. In order to detect VHL-associated tumours in time. In the CNS. further in brain stem and spinal chord.1883}. and a second tumour is seen in the lower pole. Both lesions are benign and rarely life threatening.06 VHL disease. endolymphatic sac tumours of the inner ear. and the presence of one of the typical VHL-associated extraneural tumours or a pertinent family history. Function of the VHL protein Mutational inactivation of the VHL gene in affected family members is responsible A 16 B Fig. CNS haemangioblastomas develop somewhat later (mean. and epididymal and broad ligament cystadenomas. The median life expectancy of VHL patients was 49 years {1279. Tumours of the kidney . with an onset age of 16 to 67 years {2032}. They are often associated with pancreatic cysts. Small cysts are present in the cortex. Clinical Features Renal lesions in carriers of VHL germline mutations are either cysts or CCRCC. Other extrarenal manifestations include neuroendocrine tumours. Phaeochromocytomas may constitute a major clinical challenge. Periodic screening of VHL patients by MRI should start after the age of ten years {328}.04 Familial renal carcinoma.05 Renal cell carcinoma in a patient with von Hippel-Lindau disease. particularly in VHL families with predisposition to the development of these tumours. Diagnostic criteria The clinical diagnosis of von HippelLindau disease is based on the presence of capillary haemangioblastoma in the Gene expression The VHL gene is expressed in a variety of human tissues. initial clear cell RCC. particularly in those of younger age and with multiple lesions. Metastatic RCC is the leading cause of death from VHL {2384}. Kidney tumours associated with VHL The typical renal manifestation of VHL are kidney cysts and clear-cell renal cell carcinomas (CCRCC). The diagnostic tools of choice are CT and MR imaging. respiratory and urogenital tract and endocrine and exocrine organs {500. 30 years). A Small. analyses for germline mutations of the VHL gene have been recommended in every patient with retinal or CNS haemangioblastoma.CNS or retina. Fig.2277}. Extrarenal manifestations Retinal haemangioblastomas manifest earlier than kidney cancer (mean age. immunoreactivity for pVHL is prominent in neurons. 1. 1. the gastrointestinal. Genetics The VHL gene is located at chromosome 3p25–26. In VHL disease. There is a 70% chance of developing CCRCC by the age of 70 years {1597}. Histological examination of macroscopically inconspicuous renal tissue from VHL patients may reveal several hundred independent tumours and cysts {2773}. to occur at rates of 1: 36 000 {1598} to 1: 45 500 population {1589}. Multiple kidney tumours of other histological types rule out the diagnosis of VHL {2032}.1864}.

platelet-derived growth factor (PDGFbeta). Binding of the hydroxylated subunit pVHL causes polyubiquitination and thereby targets HIF-alpha for proteasome degradation {855}. 1. The alpha domain of pVHL forms a complex with elongin B. splice site mutations and large deletions also occur {1882.421. According to its function as a tumour suppressor gene. have remained enigmatic. elongin C. 1958. VHL type 2 is usually associated with missense mutations and subdivided on the presence (type 2A) or absence (2B) of renal cell carcinoma {136. The domain of the VHL gene involved in the binding to elongin is frequently mutated in VHL-associated neoplasms {2488}. 179755 {1679}. From D.Table 1. Kaelin Jr. characterized by late onset. In contrast to loss of function variants in VHL type 1.phenotype correlations in VHL patients. Through a down-regulation of the response of cells to hepatocyte growth factor / scatter factor and reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2). Further. the beta subunit of HIF is hydroxylated on to one of two proline residues. Constitutive overexpression of VEGF explains the extraordinary capillary component of VHL associated neoplasms {1650}. The spectrum of clinical manifestations of VHL reflects the type of germline mutation. one of which points to a role of pVHL in protein degradation and angiogenesis. inactivated pVHL causes an overexpression of transmembrane carbonic anhydrases that are involved in extracellular pH regulation {1186} but the biological significance of this dysregulation remains to be assessed. Missense mutations are most common.1931}. VHL-type Phenotype Predisposing mutation Type 1 Without phaeochromocytoma 686 T -> C Leu -> Pro Type 2A With phaeochromocytoma and renal cell carcinoma 712 C -> T Arg -> Trp Type 2B With phaeochromocytoma but without renal cell carcinoma 505 T-> C Tyr -> His 658 G-> T Ala -> Ser for their genetic susceptibility to renal cell carcinoma and capillary haemangioblastoma. The beta-domain of pVHL interacts with the alpha subunits of hypoxia-inducible factor 1 (HIF-1) which mediates cellular responses to hypoxia. bilateral papillary renal cell tumours. Induction of EPO is responsible for the occasional paraneoplastic erythrocytosis in patients with kidney cancer and CNS haemangioblastoma. Cul-2 {1533. Phenotypes are based on the absence (type 1) or presence (type 2) of phaeochromocytoma. MIM No. but nonsense mutations. microdeletions / insertions. Several signalling pathways appear to be involved {1942}.02 Genotype . the transition from the G2 into quiescent G0 phase. 893. VEGF has been targeted as a novel therapeutic approach using neutralizing anti-VEGF antibody {1654}. HIF-alpha accumulates and activates the transcription of hypoxiainducible genes. transforming growth factor (TGFalpha) and erythropoietin (EPO). possibly by preventing accumulation of the cyclindependent kinase inhibitor p27 {2027}.2927}. Gene mutations and VHL subtypes Germline mutations of the VHL gene are spread all over the three exons. but the mechanisms by which the suppressor gene product. multiple. however several years later some of these cases developed other VHL manifestations. bilateral kidney tumours.J. causes neoplastic transformation. As a consequence. {855}. 2804}. the VHL protein (pVHL). Copyright © 2003 Massachusetts Medical Society. Fig. mutations predisposing to pheochromocytoma (VHL type 2) are mainly of the missense type predicted to give rise to conformationally changed pVHL {2804. VHL gene mutations are also common in sporadic haemangioblastomas and renal cell carcinomas {1268. VHL type 2C has been used for patients with only phaeochromocytoma {2201. Additional functions of the VHL protein may contribute to malignant transformation and the evolution of the phenotype of VHL associated lesions. Under hypoxic conditions or in the absence of functional VHL.2927}. It has been estimated that approximately 50% of affected family Familial renal cell carcinoma 17 .e.2028. George and W. Another study showed that only wild-type but not tumour-derived pVHL binds to fibronectin. thereby targeting cellular proteins for ubiquitinization and proteasome-mediated degradation. Recent studies in renal cell carcinoma cell lines suggest that pVHL is involved in the control of cell cycle exit. i. VHL-/renal cell carcinoma cells showed a defective assembly of an extracellular fibronectin matrix {1943}. In addition. Hereditary papillary renal carcinoma (HPRC) Definition Hereditary papillary renal carcinoma (HPRC) is an inherited tumour syndrome characterized with an autosomal dominant trait.07 Control of Hypoxia-inducible factor (HIF) by the gene product of the von Hippel-Lindau gene (pVHL). Diagnostic criteria The diagnosis of HPRC is based on the occurrence of multiple.1883}.2488} and Rbx1 {1264} which has ubiquitin ligase activity {1188}. pVHL deficient tumours cells exhibit a significantly higher capacity for invasion {1353}. Under normoxic conditions.G. including vascular endothelial growth factor (VEGF).

2632}. there are no guidelines yet. The histological pattern has Hereditary leiomyomatosis and renal cell cancer (HLRCC) Definition Hereditary leiomyomatosis and renal cell cancer (HLRCC.10 Hereditary papillary renal cell carcinoma (HPRC) A Tumours have a papillary or tubulo-papillary architecture very similar to papillary renal cell carcinoma. Management For patients with confirmed germline mutation. annual abdominal CT imaging is recommended. Fig.2632}. Diagnostic criteria The definitive diagnosis of HLRCC relies on FH mutation detection. Genetics Responsible for the disease are activating mutations of the MET oncogene which maps to chromosome 7q31. whether the surveillance should be carried out in all FH mutation families.1213.1450.1329. Regular screening for kidney cancer is recommended. median 36 years in the Finnish and 44 years in the North American patients. Computer tomography and abdominal ultrasound have been proposed {1328. The most patients have died of metastatic disease within five years after diagnosis. The presence of multiple leiomyomas of the skin and the uterus papillary type 2 renal cancer. 2632}. 26 patients with renal carcinomas have been identified in 11 families out of 105 (10%) {52.2327. three patients were identified having either collective duct carcinoma or oncocytic tumour {52. Leiomyomas of the skin and uterus Leiomyomas of the skin and uterus are the most common features of HLRCC. Predisposition to renal cell carcinoma and uterine leiomyosarcoma is present in a subset of families. 605839 {1679}. It is characterized by predisposi- A B Fig. ie the tyrosine kinase domain causes a ligand-independent constitutive activation. Most tumours stain positive for vimentin and negative for cytokeratin 7. as renal cell carcinoma is present only in a subset of families. and early-onset uterine leiomyosarcoma are suggestive {51.2032. The peculiar histology of renal cancers in HLRCC originally led to identification of this syndrome {1450}.1450. Macrophages are frequently present in the papillary cores.08 Hereditary papillary renal cancer (HPRC) with multiple. B Hereditary papillary renal cell carcinoma frequently react strongly and diffusely with antibody to cytokeratin 7.been termed papillary renal carcinoma type 1 and is characterized by papillary or tubulo-papillary architecture very similar to papillary renal cell carcinoma. Papillary renal cell carcinoma BHD patients develop myriad papillary tumours.1570. 2632}. type 1. 2937}.1996.1212.2632}. and uterine leiomyomas from 1852 years (mean 30 years) {2632}. HLRCC renal cell carcinomas display papillary type 2 histology and large cells with abundant eosinophilic cytoplasm. Recently. The onset of cutaneous leiomyomas ranges from 10-47 years. Extrarenal manifestations of HPRC have not been identified. the penetrance being approximately 85% {1328.09 Germline mutations of the MET oncogene in hereditary papillary renal cell carcinoma (HPRC). MIM No. 1. bilateral papillary RCC. Mutations in exons 16 to 19. members develop the disease by the ago of 55 years {2327}. 18 Tumours of the kidney .1469. large nuclei. Its ligand is hepatocyte growth factor (HGFR). 2928}.2326. type 1. The Fuhrman nuclear grade is from 3 to 4.52. MIN no: 605839) is an autosomal dominant tumour syndrome caused by germline mutations in the FH gene. but optimal protocols have not yet been determined. Clinically. 1.1330. The average age at onset is much earlier than in sporadic kidney cancer. Moreover.845. 1. 2632}. Duplication of the mutant chromosome 7 leading to trisomy is present in a majority of HPRC tumours {768. MET codes for a receptor tyrosine kinase {799.1469.2926. tion to benign leiomyomas of the skin and the uterus. ranging from microscopic lesions to clinically symptomatic carcinomas {1979}. Typically. cutaneous leiomyomas present Fig. Renal cell cancer At present. and prominent inclusion-like eosinophilic nucleoli. The carcinomas are typically solitary and unilateral {1450. (range 18-90 years).

The first exon encodes a mitochondrial signal peptide. Uterine leiomyomas in HLRCC are often numerous and large. eosinophilic cytoplasm. {661. they are composed of interlacing bundles of elongated. Uterine leiomyomas are well-circumscribed lesions with firm and fibrous appearance. The cases have been diagnosed at 30-39 years. The tumours are densely cellular and display spindle cells with blunt-ended nuclei.11 A Multiple cutaneous leiomyomas in a female HLRCC patient. large pseudostratified nuclei and prominent nucleoli. B Thick papillae are covered by tall cells with abundant cytoplasm. Genetics Gene structure and function FH is located in chromosome 1q42. Leiomyomas with atypia may also occur. However. consists of 10 exons.12 Hereditary leiomyoma renal cell carcinoma (HLRCC).2623}. A Renal cell carcinoma from a 50 year old female patient displaying papillary architecture resembling papillary renal cell carcinoma. Histologically.662. magnification x10). 1. and a variable degree of differentiation. Mitochondrial FH acts in the tricarboxylic acid (Krebs) cycle catalyzing conversion of fumarate to malate. 1. as multiple firm. FH is also known to be involved in the urea cycle. B Fumarate hydratase (FH) gene mutations in HLRCC and FH deficiency. Uterine leiomyosarcomas invade the adjacent myometrium and are not well demarcated from normal tissue. the role of cytosolic FH is still somewhat unclear. Cutaneous leiomyomas are composed of interlacing bundles of smooth muscle cells with centrally located blunt-ended nucleus.3q43.1469}.A B Fig. and encodes a 511 amino acid peptide. Leiomyosarcoma of the uterus Predisposition to uterine leiomyosarcoma is detected in a subset of HLRCC families (3 out of 105 families) {1450. but processed FH (without the signal peptide) is present also in the cytosol. Mutated codons identified in the families with RCC and/or uterine leiomyosarcoma are indicated. skin-coloured nodules ranging in size from 0. Biallelic inacti- A B Fig.5-2 cm. Familial renal cell carcinoma 19 . type 2 (H&E staining. eosinophilic smooth muscle cells surrounded by well-vascularized connective tissue.

resembling mainly chromophobe and clear cell renal carcinomas and renal oncocytomas as well as fibrofolliculomas and pulmonary cysts {246. Multiple renal tumours and spontaneous pneumothoraces are frequent in patients with BHD syndrome.2632}. a missense mutation H153R (in 3 out of 7 families) and a 2-bp deletion in codon 181 (in 3 out of 7 families). Definition Birt-Hogg-Dubé (BHD) syndrome is a syndrome characterised by benign skin tumours. MIM No. Renal oncocytoma is well described and is usually thought of as a benign tumour.1469. Genotype-phenotype correlations No clear pattern has emerged to date.1469.2632}.2627}.1330.2627. and others little or no risk. a missense mutation R190H was reported in 35% of the families from North America. B A C Fig. Metastatic disease is rare and appears to only occur if the primary tumour has a diameter of >3 cm {2031}.1330. trichodiscomas (TD) and acrochordons are the classical skin lesions in BHD syndrome. Renal cell cancer and uterine leiomyosarcoma occur only in a minority of families. but the same mutations (a 2-bp deletion in codon 181. Diagnostic criteria Renal tumours Renal pathology may vary in individuals with BHD syndrome. growth and developmental delay.2033.1330. the role of FH in sporadic tumorigenesis has been evaluated in three different studies {169.13 A Early facial fibrofolliculomas in BHD syndrome. and H275Y) have been identified in families with or without malignancies.1450}. reduced enzyme activity in all tissues.C CT scan images of abdomen in BHD patient showing multiple bilateral renal carcinomas which necessitated bilateral nephrectomy and subsequent renal transplant. Somatic FH mutations seem to be rare. Tumours can be multiple and bilateral. 1. Biopsy will usually demonstrate an epidermis with aberrant follicular structures. The syndrome is characterized by neurological impairment.1469}. Because some families appear to have high risk of cancer at early age. Thus far. Heterozygous parents are neurologically asymptomatic heterozygous carries of the mutation with a reduced enzyme activity (approximately 50%). To date.). 10 different FH mutations have been reported in 14 FH deficiency families (Fig 3.2627. vation of FH has been detected in almost all HLRCC tumours {52. R190H. Other lesions Spontaneous pneumothorax and the 20 Tumours of the kidney . Acrochordons (skin tags) are not always present. Other histopathologies have been described including papillary and chromophobe adenocarcinoma with a mixed population of clear and eosinophillic cells. Tumour predisposition similar to HLRCC is likely {2627}. In addition. The FF and TD lesions look the same and present as smooth dome-shaped. Two founder mutations have been detected in the Finnish population. modifying gene/s could play a key role in the development of renal cancer and uterine leiomyosarcoma in HLRCC {697. B. A splice site mutation IVS4+1G>A was detected in families of Iranian origin {465}. R190C.2924}.1891. but have been found in uterine leiomyomas and a high-grade sarcoma. 135150 {1679}. Three mutations (K187R. skin coloured papules up to 5mm in diameter over the face. neck and upper body with onset typically in the third or fourth decade of life. 2631. Most of the families with these mutations included renal cell cancer and/or uterine leiomyosarcoma {1330. FH mutations Germline mutations in FH have been found in 85% (89/105) of the HLRCC families {52. thin columns of epithelial cells and small immature sebocytes clustered within the epithelial cords. Altogether 50 different germline mutations have been identified.1329. Skin lesions are initially subtle but remain indefinitely and become more obvious with increasing age as illustrated by Toro et al 1999 {2631}. and R190H) have been reported in both HLRCC and FH deficiency. specifically fibrofolliculomas. trichodiscomas and acrochordons. FH deficiency This is a recessive disease caused by biallelic germline mutations in FH. Alcian blue demonstrates the presence of abundant mucin within the stroma. fumaric aciduria and absent or Birt-Hogg-Dubé syndrome (BHD) The BHD syndrome conveys susceptibility to develop renal epithelial tumours Skin tumours Fibrofolliculomas (FF). The age at clinical manifestation is approximately 50 years and the mean number of tumours present is 5 per patient.

2 {1306. {862} Zajaczek et al.5 Reference t(3:8)(p14:q24) t(3:6)(p13:q25. there may be a slight increase in the incidence of other neoplasia although this remains unclear {1307}. Multiple lipomas and mucosal papules have been described {2361}. {2695}. A mutational hot spot present in more than 40% of families was identified in a tract of 8 cytosines {2032}.2328}. For those with skin features or found to have the characteristic dermatological features. 144700 {1679}. {1355} Geurts van Kessel et al. Table 1. Management Surveillance for all first-degree relatives of an affected individual is advocated. MIM No. Diagnostic criteria Occurrence of single or multiple.i. B Small cluster of clear cells is surrounded by normal tubules. t(1:3)(q32:q13. {862} Geurts van Kessel et al. A reported association with colonic neoplasia has not been confirmed in subsequent studies. characterized by an increased risk of developing renal cell carcinomas (RCC).1) t(2:3)(q35:q21) t(3:6)(q12:q15) Cohen et al. It codes for a novel protein called folliculin whose function is unknown currently {1891}. Affected family members typically show frameshift mutations. {2917} Kanayama et al.03 Familial renal cell cancer associated with chromosome 3 constitutional translocation. Genetics BHD syndrome is a rare autosomal dominant condition with incomplete penetrance. From F. annual renal MRI scan would be the investigation of choice to detect any renal malignancy at as early a stage as possible and to facilitate minimal renal surgery where possible to conserve renal function. van Erp et al.A B Fig. {476} Kovacs et al {1371} Koolen et al.14 Birt-Hogg-Dubé syndrome (BHD). ie insertions.3) 4 4 66. A Hybrid oncocytic tumour composed of a mixture of clear cells and cells with abundant eosinophilic cytoplasm. repeated examinations involving ionising radiation may carry a risk of inducing malignancy. The association of RCC with a chromosome 3 translocation alone is not diagnostic since this genetic alteration is also observed in sporadic cases. Constitutional chromosome 3 translocations Definition Inherited cancer syndrome caused by constitutional chromosome 3 locations with different break points. Skin examination to determine diagnosis from the third decade. {1265} t(3:4)(p13:p16) 1 3 52 t(2:3)(q33:q21) 7 3 n. In tumour predisposition syndromes where a second somatic muta- tion in the normally functioning wild type gene will leave no functioning protein in the cell. stop codons. These lesions can be found scattered through the renal parenchyma. presence of pulmonary cysts are recognised features of BHD syndrome. 1. Pathology Tumours show histologically the typical features of clear cell RCC. Translocation Number of RCC cases 10 1 5 4 Generations Involved 4 3 3 4 Mean age 44 50 47 57. deletions {1891}.7 Familial renal cell carcinoma 21 . The BHD gene maps to chromosome 17p11. LOH analyses and assessment of promoter methylation indicate that BHD is also involved in the development of a broad spectrum of sporadic renal cancers {1308}. unilateral or bilateral RCC in a member of a family with a constitutional chromosome 3 translocation.

22 Tumours of the kidney .6)(p13. In a second RCC family a t(3. Seven families have now been reported. Loss of the derivative chromosome 3 through genetic instability is considered the first step in tumour development.q24) was reported {1374}. However. The mode of inheritance is autosomal dominant. Affected family members carry a balanced chromosomal translocation involving chromosome 3.8)(p14. this mechanism involving VHL is hypothetical as affected family members do not develop extra-renal neoplasms or other VHL manifestations. The identification of at least 7 families strongly supports the notion that constitutional chromosome 3 translocations may substantially increase the risk to develop renal cell carcinoma and this should be taken into account in the framework of genetic counselling.q24). resulting in a single copy of VHL.q25) was found to segregate and. only one person in the first generation developed multiple bilateral RCCs {1371}. a single sporadic case with a constitutional t(3. Translocations vary among different families and this may affect penetrance. Fig. 1. Additionally. {2695}. as yet.12)(q13. {476} with 10 RCC patients over 4 generations. breakpoint frequencies (%) of chromosome 3 translocations in 93 Dutch families are shown (grey bars). From F. On the right side.15 Diagram of chromosome 3 with seven constitutional chromosome 3 translocations and the respective breakpoint positions (left). van Erp et al. in addition to somatic chromosome 3 translocations in 157 sporadic RCCs (black bars). translocations are different but in all families the breakpoints map to the proximal p-and q-arms of chromosome 3.Genetics The first family was described by Cohen et al. The remaining VHL copy may then be mutated or otherwise inactivated. All patients were carriers of a t(3.

testicularis/v. or along the ureter may also occur. necrosis. the v. rounded luminal space filled with lightly acidophilic serous fluid or erythrocytes occurs in the A B C Clear cell renal cell carcinoma Fig. Retrograde metastasis along the paravertebral veins. 23 .16 Clear cell renal cell carcinoma. Multicentricity and bilaterality and early age of onset are typical of hereditary cancer syndromes such as von Hippel-Lindau syndrome. The carcinomas typically contain a regular network of small thin-walled blood vessels. Some renal neoplasms of this morphology are now included among the clear cell type. haemorrhage. bosselated mass. ter ten years or more. ovarii. All kidney tumours of the clear cell type are considered malignant tumours. {2514}. Clear cell RCC is well known for its propensity to metastasize to unusual sites. Macroscopy Clear cell renal cell carcinomas (RCCs) are solitary and randomly distributed cortical tumours that occur with equal frequency in either kidney. although lymphatic metastases also occur. alveolar and acinar patterns. Although not formally part of the nuclear grading system. Bonsib H. Moch (unpublished). Historically. grade has a strong predictive power. A. Clear cell RCCs most commonly metastasize hematogenously via the vena cava primarily to the lung. Cysts. Prognosis of patients with clear cell RCC is most accurately predicted by stage. Within stages. Diffuse infiltration of the kidney is uncommon. the terms Grawitz tumour and hypernephroma have also been used for clear cell renal cell carcinoma.N. Histopathology Clear cell RCC is architecturally diverse. The interface of the tumour and the adjacent kidney is usually well demarcated. is not uncommon.822}.M. Grignon J. Moch Definition Clear cell renal cell carcinoma is a malignant neoplasm composed of cells with clear or eosinophilic cytoplasm within a delicate vascular network. but similar appearing cells occur in other tumour types. Tumour spread and staging About 50% of clear cell RCCs are stage 1 and 2 and less than 5% stage 4. intrarenal veins. 1. Calcification and ossification occur within necrotic zones and have been demonstrated radiologically in 10 to 15 percent of tumours {209. with a "pushing margin" and pseudocapsule. neutral lipids. even af- Fig. H. Eble S.B. with solid. many of these patients dying in less than 12 months. and calcification are commonly present. Clear cell RCCs are typically globular tumours which commonly protrude from the renal cortex as a rounded.J. a diagnostically helpful characteristic of this tumour. 1. Recognition of stage pT3a requires detection of tumour cells in direct contact with perinephric or renal sinus fat. Size itself is not a determinant of malignancy though increasing size is associated with a higher frequency of metastases. sarcomatoid change has a strongly negative effect. The average size is 7 cm in diameter but detection of small lesions is increasing in countries where radiologic imaging techniques are widely applied. and phospholipids are abundant. and so the term "granular cell renal cell carcinoma" should no longer be used. cholesterol. The clear cell renal cell carcinoma is typically golden yellow due to the rich lipid content of its cells.Clear cell renal cell carcinoma D. Multicentricity and/or bilaterality occur in less than 5 percent of cases {1193}. No lumens are apparent in the alveolar pattern but a central. Invasion of perirenal and sinus fat and/or extension into the renal vein occurs in about 45% {1753}. the most common.17 Frequency of organ involvement by haematogenous metastasis in patients with metastatic renal cell carcinoma (n=636) at autopsy. and late metastasis.C Variable macroscopic appearances of the tumours. ICD-O code 8310/3 Synonym The term "granular cell renal cell carcinoma" was used for many years for renal cell carcinomas with eosinophilic cytoplasm and high nuclear grade {1845}.

High molecular weight cytokeratins. Typical alveolar arrangement of cells. Sarcomatoid change occurs in 5% of tumours and is associated with worse prognosis.2880}. The 4-tiered nuclear grading system {815} is as follows: Using the 10x objective. the nucleoli must be easily unequivocally recognizable with the 10x objective. this is particularly common in high grade tumours and adjacent to areas with necrosis or haemorrhage. CK18. nucleoli may be inconspicuous. CD10 {140} and epithelial membrane antigen {776}. The prognostic value of nuclear grade has been validated in numerous studies over the past 8 decades. Most clear cell RCCs have little associated inflammatory response.1760.1445. Scattered cells may be discounted but if several cells within a single high power focus have high grade characteristics. 3p deletions have been described in the vast majority of sporadic clear cell renal cell carcinoma by conventional cytogenetic. infrequently. 1. areas of calcification or ossification {991}. clear cell renal cell carcinoma has a distinct tubular pattern and rarely a pseudopapillary architecture is focally present. small.1082.2086. CK19.2109. Very large nuclei lacking nucleoli or bizarre nuclei may occasionally occur. Grading Nuclear grade. FISH. or epigenetic silencing in 70% or more {897.1786.949. Cam 5. 2691.2400. MUCΙ and MUC3 are consistently expressed {1479}. then the tumour should be graded accordingly.792. grade 1 cells have small hyperchromatic nuclei (resembling mature lymphocytes) with no visible nucleoli and little detail in the chromatin. The majority of clear cell RCCs react positively for renal cell carcinoma marker {1675}. renal carcinoma. Mutations of the VHL gene have been described in 34-56% of sporadic clear cell RCC {307. or large and prominent. the nuclei tend to be round and uniform with finely granular. A B Fig. creating a clear cytoplasm surrounded by a distinct cell membrane. CK8. LOH and CGH analyses {1372.18 A VHL. producing microcystic and macrocystic patterns.2686}.2614. A host of unusual histologic findings are described in clear cell renal cell carcinoma. and 34βE12 are rarely detected. In well preserved preparations.897. an intense lymphocytic or neutrophilic infiltrate is present. Grade is assigned based on the highest grade present. which are dissolved in routine histologic processing.2690. Immunoprofile Clear cell RCCs frequently react with antibodies to brush border antigens. somatic inactivation of the VHL gene may occur by allelic deletion.acinar pattern.2723. Note clear cells and cysts. Somatic genetics Although most clear cell RCCs are not related to von Hippel Lindau disease. Therefore. Some tumours have central areas of fibromyxoid stroma. hyperchromasia and single to multiple macronucleoli.2925}. AE1. These data suggest that the VHL gene is the most likely candidate for a tumour suppressor gene in sporadic clear cell RCC. 815. These data suggest involvement of multiple loci on chromosome 3 in renal cancer development {474.1754.2433.764.2810}. one at 3p21-22 {2689} and one at 3p13-14 {2721}. low molecular weight cytokeratins. mutation. Nuclear grade 4 is characterized by nuclear pleomorphism. The cytoplasm is commonly filled with lipids and glycogen. after stage.2342.2818. The alveolar and acinar structures may dilate. which includes the chromosomal translocation point in familial human renal cell carcinoma. DNA methylation was observed in 19% of clear cell renal cell carcinomas {1082}. 24 Tumours of the kidney . Depending upon the grade. is the most important prognostic feature of clear cell renal cell carcinoma {441.2473.2940}. including CK14 {464}.2342}. Many tumours contain minority populations of cells with eosinophilic cytoplasm. B Clear cell renal cell carcinoma. Infrequently. Genetic susceptibility Clear cell renal cell carcinoma constitutes a typical manifestation of von Hippel-Lindau disease (VHL) but may also occur in other familial renal cell cancer syndromes.2 and vimentin {1675.2400}. Both 4-tiered and 3tiered grading systems are in widespread use. evenly distributed chromatin. For nuclear grade 3. At least 3 separate regions on chromosome 3p have been implicated by LOH studies as relevant for sporadic renal cell carcinoma: one coincident with the von Hippel-Lindau (VHL) disease gene locus at 3p25-26 {1445. Grade 2 cells have finely granular "open" chromatin but inconspicuous nucleoli at this magnification.

Lohse et al.. 1. High level gene amplifications are rare in clear cell renal cell carcinoma {1754}. IL-8.1472.339.21 Clear cell carcinoma. neo-vascularization. and one signal in green (VHL gene). Whereas Fig. Chromosome 3p deletions have been observed in very small clear cell tumours of the kidney and are regarded as the initial event in clear cell cancer development {2107.1080.2179. HER2/neu amplifications are rare or absent in renal cell carcinoma {2339.2345}.2849}. A few studies suggest that p53 overexpression is associated with poor prognosis and with sarcomatoid transformation {1932. {1532}. From C. Losses of chromosome 14q were correlated with poorer patient outcome. to sarcomatoid differentiation in <50% (n=37) and >50% (n=31) of tumour area. MHC class II and E-cadherin may be important for development and/or progression {320. The role of p53 expression in renal cell carcinoma is controversial. this pathway is uncommon in renal cell carcinoma {1756}. From H. Copyright © 2000 American Cancer Society. Reprinted by permission of WileyLiss.19 Clear cell RCC.1310. However. 1. Expression levels of many genes have been studied in clear cell RCC.2925}. cDNA array analysis of clear cell renal carcinoma showed complex patterns of gene expression {1759. LOH on chromosome 10q around the PTEN/MAC locus have been frequently detected and were related to poor prognosis {2722}. MMP-2. Fig.2164. MMP-9. 1. Expression of epidermal growth factor receptor (EGFR) is frequent in renal cell carcinoma and has been proposed as prognostic parameter {1755}.2341}. amplification of the EGFR gene on chromosome 7p13 is a major cause for EGFR expression in brain tumours.2109.958. {1753}.2799}. there are two signals in red (chromosome 3). Inactivation of the VHL gene has consequences for VHL protein function. recent data give evidence for other putative tumour suppressor genes at 3p. Note deletion of 3p as the only karyotype change. Inc.1939.2437}. Survival curves by grade for patients with clear cell renal cell carcinoma. It has been shown that the integration of expression profile data with clinical data could serve to enhance the diagnosis and prognosis of clear cell RCC {2551}. High expression levels of bFGF. Clonal accumulation of additional genetic alterations at many chromosomal locations then occurs in renal cancer progression and metastasis {247. 1218. Clear cell renal cell carcinoma 25 . Individual chromosomal gains and losses have been analyzed for an association with patient prognosis.Fig.g. Survival of patients depends on the presence and extent of sarcomatoid differentiation. 2344.1828}.M. The VHL protein negatively regulates hypoxia-inducible factor. 2659}. Fig.2887}. and extracellular matrix formation {642. which activates genes involved in cell proliferation. VHL deletion. Inc. e. RASSF1A at 3p21 {1789} and NRC-1 at 3p12 {1562}. Moch et al. FISH expression. a subsidiary of John Wiley & Sons. high histologic grade and high pathologic stage {226.22 Clear cell RCC. ranging from no differentiation (n=326).2391. 1.2344.20 Clear cell renal cell carcinoma.1754. Chromosome 9p loss seems to be a sign of poor prognosis {1754.1892.2109. vimentin. VEGF.

1. A The septa of multilocular cystic renal cell carcinoma contain eptihelial cells which can be mistaken for lymphocytes.24 Multilocular cystic renal cell carcinoma. the septa of which contain small groups of clear cells indistinguishable from grade Ι clear cell carcinoma. and have dense chromatin. do not form expansile nodules. The nuclei almost always are small. mean = 51) {650}. Macroscopy While cysts are common in clear cell renal cell carcinomas. Diameters have ranged from 25 mm to 130 mm. ICD-O code 8310/3 small and large cysts filled with serous or haemorrhagic fluid and separated from the kidney by a fibrous capsule. Histopathology The cysts are usually lined by a single layer of epithelial cells or lack an epithelial lining. 26 Tumours of the kidney .N. These epithelial cells often closely resemble histiocytes. EMA expression. Multilocular cystic renal cell carcinoma consists of a well-circumscribed mass of Fig. only rarely is the tumour entirely composed of cysts. No instance of progression of multilocular cystic renal cell carcinoma is known. ones containing expansive nodules of carcinoma must be excluded and diagnosed simply as clear cell renal cell carcinoma {650}. In order to distinguish these tumours with excellent outcomes from other clear cell carcinomas.23 Multilocular cystic renal cell carcinoma. Occasionally. Eble Definition A tumour composed entirely of numerous cysts. All have been adults (age range 2076 years. 1. In these tumours the number of carcinoma cells is small and diagnosis is challenging {1835}. A B Fig. Immunoprofile The cells with clear cytoplasm in the septa frequently react strongly with antibodies to cytokeratins and epithelial membrane antigen and fail to react with antibodies to markers for histiocytes. often densely collagenous. the lining consists of several layers of cells or a few small papillae are present {2561}. The epithelial cells resemble those lining the cysts and almost always have small dark nuclei. or lymphocytes surrounded by retraction artefacts. Within some of the septa there is a population of epithelial cells with clear cytoplasm. Increased vascularity within the cell clusters is a clue to their nature. More than 20% have calcification in the septa and osseous metaplasia occasionally occurs. The lining cells may be flat or plump and their cytoplasm ranges from clear to pale. B The epithelial cells in the septa of multilocular cystic renal cell carcinoma react with antibodies to epithelial markers.Multilocular cystic renal cell carcinoma J. The septa consist of fibrous tissue. spherical. Tumour spread and staging No tumour with these features has ever recurred or metastasized. The clear cells form small collections but Clinical features There is a male:female predominance of 3:1.

1693. Tumour lined cysts with papillary excrescences may also be seen {585. Calcified concretions are common in papillary cores and adjacent desmoplastic stroma. Antibody Number of cases % showing positive expression 100 100 45 51 55 92 3 11 93 93 0 AE1/AE3 CAM 5.2169}.8:1 to 3. Sarcomatoid dedifferentiation is seen in approximately 5% of PRCC and has been associated with both type 1 and type 2 tumours {585}. this is more frequently observed in type 1 (87%) than type 2 (20%) tumours {585}.04 Immunohistochemical profile of PRCC. Two morphological types of PRCC have been described {585}: Type 1 tumours have papillae covered by small cells with scanty cytoplasm.N. The tumour papillae contain a delicate fibrovascular core and aggregates of foamy macrophages and cholesterol crystals may be present. Grading There is no specific grading system for PRCC and the Fuhrman system {815} is accepted as applicable to both clear cell renal cell carcinoma and PRCC. while calcium oxalate crystals have been reported {587. Necrosis and haemorrhage is frequently seen and haemosiderin granules may be present in macrophages.584. Ultrastructural findings are not diagnostic and are similar to clear cell renal cell carcinoma {1888.1612}. Delahunt J. The age and sex distribution of PRCC is similar to clear cell renal cell carcinoma with reported mean age at presentation and sex ratio (M:F) for large series ranging from 52-66 years and 1. Table 1. 1612}.1860}. necrosis and cystic degeneration. 1.2169}.2 EMA Vimentin S-100 Callus 34βE12 CEA RCC CD-10 Ulex europeaus ________ 36 11 11 116 11 36 36 36 14 14 105 From {140. Histopathology PRCC is characterized by malignant epithelial cells forming varying proportions of papillae and tubules.8:1.585. ICD-O code 8260/3 Epidemiology Papillary renal cell carcinomas (PRCC) comprise approximately 10% of renal cell carcinoma in large surgical series {584.2609}.641. although renal angiography studies have shown relative hypovascularity for PRCC {1860}. Macroscopy PRCC frequently contains areas of haemorrhage. and in well-circumscribed tumours an investing pseudocapsule may be identified {76.1612. Type 1 tumours are more frequently multifocal. Eble Definition A malignant renal parenchymal tumour with a papillary or tubulopapillary architecture. B Gross specimen showing tumour haemorrhage and pseudoencapsulation. A The papillary architecture is faintly visible in the friable tumour. Occasionally the papillary cores are expanded by oedema or hyalinized connective tissue {584.831. Multilocular cystic renal cell carcinoma / Papillary renal cell carcinoma 27 . arranged in a single layer on the papillary basement membrane. stroma and tumour cell cytoplasm {1612}. Immunoprofile Cytokeratin 7 (CK 7) expression has been reported for PRCC {831} however.585}.1860}. C Yellow streaks reflect the population of foamy macrophages.25 Papillary renal cell carcinoma.Papillary renal cell carcinoma B.587. Solid variants of PRCC consist of tubules or short papillae resembling glomeruli {585.2173}. Bilateral and multifocal tumours are more common in PRCC than in other renal parenchymal malignancies and in hereditary PRCC up to 3400 microscopic tumours per kidney have been described {1979. respectively {76. Radiological investigations are non-specific. A B C Fig. Clinical features Signs and symptoms are similar to clear cell renal cell carcinoma {1612}.1612}. Type 2 tumour cells are often of higher nuclear grade with eosinophilic cytoplasm and pseudostratified nuclei on papillary cores.

1753} Fig.1373}. trisomy 17 and loss of chromosome Y are the common- est karyotypic changes in PRCC {1373}. High resolution studies have shown interstitial 3p loss of heterozygosity in some PRCC {1789. A Type 1 PRCC with foamy macrophages in papillary cores.1612}. FISH technique. 28 Tumours of the kidney .1753}. Somatic genetics Trisomy or tetrasomy 7. 1.27 A Papillary carcinoma.1753} and the presence of sarcomatoid dedifferentiation {76. Longer survivals have been demonstrated for type 1 when compared with type 2 PRCC on both univariate {1753} and multivariate analysis that included both tumour stage and grade {587}. 1. many pathologists prefer to report them as "papillary epithelial neoplasm of low malignant potential" for practical reasons.1612. type 2. while on multivariate modelling only tumour stage retained a significant correlation with survival {76}. Comparative genomic hybridization studies show more gains of chromosomes 7p and 17p in type 1 PRCC when compared to type 2 tumours {1219}. differing patterns of allelic imbalance at 17q and 9p have been noted {2291}. B Type 1 PRCC showing a compact tubulopapillary pattern.28 Papillary carcinoma.26 Type 1 Papillary renal cell carcinoma. Chromosome 17 trisomy.587. Large cells with eosinophilic cytoplasm in type 2 papillary RCC. 675. while more recently.1428.585. Prognosis and predictive factors In series of PRCC containing both type 1 and 2 tumours. five year survivals for all stages range from 49% to 84% {584. Trisomy of 12. Additionally the presence of extensive tumour necrosis and numerous foamy macrophages has been associated with a more favourable prognosis {76. While grade 1 tubulopapillary tumours between 0.1428.1753}.5 and 2 cm are strictly defined as carcinomas. 1612}. Tumour cells show nuclear pseudostratification and eosinophilic cytoplasm. Up to 70% of PRCC are intrarenal at diagnosis {76. with tumour grade {76.2723}. typical for papillary RCC.A B Fig. 16 and 20 is also found in PRCC and may be related to tumour progression {618. B Type 2 Papillary renal cell carcinoma. while loss of heterozygosity at 9p13 is associated with shorter survival {2340}.1860} and type 1 tumours are usually of lower stage and grade than type 2 tumours {76. A B Fig. 1. stage at presentation {76. being correlated with outcome.

16. Lohse et al. {1532}.29 Papillary renal cell carcinoma. 12. 1. From C.M. B Survival curves by grade for patients with papillary renal cell carcinoma. A Trisomy 7. 13. 17 and 20 and deletion of 21 and Y. Papillary renal cell carcinoma 29 .A B Fig.

eosinophilic variant. Sporadic and hereditary forms exist.30 Chromophobe renal cell carcinoma (RCC). Note binucleated cells. 1. Störkel G. Mortality is less than 10% {512}. A B Fig. B Note chromophobe and eosinophilic cells. A B Fig. Clinical features There are no specific signs and symptoms. these are mostly large masses without necrosis or calcifications. 1. The mean age of incidence is in the sixth decade. Typical homogeneously tan coloured tumour of the lower pole of the kidney. Note typical granular cytoplasm with perinuclear clearance. with a range in age of 27-86 years. Macroscopy Chromophobe renal cell carcinomas are solid circumscribed tumours with slightly lobulated surfaces. B Chromophobe RCC. In unfixed specimens the cut surface is homogeneously light Epidemiology Chromophobe renal cell carcinoma (CRCC) accounts for approximately 5 per cent of surgically removed renal epithelial tumours.Chromophobe renal cell carcinoma S. ICD-O code 8317/3 equal. and the number of men and women is roughly Fig. 30 Tumours of the kidney .32 A Chromophobe RCC. On imaging. A Chromophobe cells are arranged along vascular channels.31 Chromophobe RCC. perinuclear halos and tight intercellular cohesion. Martignoni E. van den Berg Definition Renal carcinoma characterized by large pale cells with prominent cell membranes. 1.

2172}. many of the blood vessels are thick-walled and eccentrically hyalinized. Chromophobe renal cell carcinoma is characterized by large polygonal cells with transparent slightly reticulated cytoplasm with prominent cell membranes. sometimes glandular. Some are binucleated. Somatic genetics Chromophobe renal cell carcinomas are characterized by extensive chromosomal loss. In contrast to clear cell renal cell carcinoma. Fig. vimentin-. most frequently -1. B Fig. nuclei. Endoreduplication/polyploidization of the hypodiploid cells has been observed.-2. EMA+ (diffuse). only 4% show involvement of the renal vein (T3b) {512}.-17 and –21 {338.36 Chromophobe renal cell carcinoma.1635. often wrinkled. with focal calcifications and broad fibrotic septa. FISH.-13. Nucleoli are usually small.1675. At the molecular level. Sarcomatoid transformation occurs {2047}.A Fig. the cytoplasm is crowded by loose glycogen deposits and numerous sometimes invaginated vesicles. A representative karyotype of a chromophobe RCC showing extensive loss of chromosomes.-6. The perivascular cells are often enlarged. Another diagnostic hallmark is a diffuse cytoplasmic staining reaction with Hale’s colloidal iron stain {475. {486} showed that there are mutations of Immunoprofile Immunohistology presents the following antigen profile: pan-Cytokeratin+. The massive chromosomal losses lead to a hypodiploid DNA index {42}. CD10– {140. liver and pancreas) have been described {152. 150-300 nm in diameter resembling those of the intercalated cells type b of the cortical collecting duct {722. The eosinophilic variant of chromophobe carcinoma is purely composed of intensively eosinophilic cells with prominent cell membranes {2610}. 1. B Classic variant.-10. 1. Telomeric associations and telomere shortening have also been observed {1113.35 Chromophobe RCC with typical monosomy (one signal for chromosome 17). A Hale’s iron staining of eosinophilic variant.1375}. A few cases of lymph node and distant metastasis (lung. Histopathology In general. These cells are commonly mixed with smaller cells with granular eosinophilic cytoplasm. Fig. 1. 1. parvalbumin+. RCC antigen-/+.33 Chromophobe RCC with sarcomatoid dedifferentiation.2515}. Ultrastructure Electron microscopically. brown or tan turning light grey after formalin fixation.2513}. Perinuclear halos are common. Tumour spread and staging The majority of CRCCs are stage T1 and T2 (86%) whereas only 10% show extension through the renal capsule into surrounding adipose tissue.2464}.1635. The cells have irregular. Chromophobe renal cell carcinoma 31 . Contractor et al.34 Chromophobe RCC.2608}. the growth pattern is solid. lectins+. Hale’s colloidal iron stain positivity in the cytoplasm.

Fig. Prognosis and predictive factors Sarcomatoid phenotype is associated with aggressive tumour growth and the development of metastasis. {1532}.38 Chromophobe renal cell carcinoma. A B Fig. 1. B The perinuclear rarefaction and peripheral condensation of mitochondria responsible for the perinuclear halos. Survival curves by grade for patients with chromophobe renal cell carcinoma.TP53 tumour suppressor gene in 27% of the chromophobe RCCs.3 chromosomal region. 32 Tumours of the kidney . Sükösd et al. A Electron micrograph showing the numerous cytoplasmic microvesicles and thick cytoplasmic membranes.37 Chromophobe renal cell carcinoma. 1.M. Lohse et al. From C. {2531} demonstrated loss of heterozygosity (LOH) around the PTEN gene at the 10q23.

1. Moch Definition A malignant epithelial tumour thought to be derived from the principal cells of the collecting duct of Bellini. ICD-O code 8319/3 ly have a firm grey-white appearance with irregular borders {2470}.2262. When small. Histopathology The diagnosis of collecting duct carcinoma is often difficult and to some extent is Synonym Collecting duct carcinoma. B Tubular type of growth. 1. C Fig. other common forms of renal cell carcinoma (clear cell. about 55) with a male to female ratio of 2:1 {2470}. lung. Some tumours grow as masses within the renal pelvis. Upper tract imaging often suggests urothelial carcinoma and patients may occasionally present with positive urine cytology. origin within a medullary pyramid may be seen. papillary) may also arise centrally from cortical tissue of the columns of Bertin.Carcinoma of the collecting ducts of Bellini J. Carcinoma of the collecting ducts of Bellini 33 . bone and adrenal gland are common. accounting for <1% of renal malignancies. Reported tumours range from 2. About onethird of patients have metastases at presentation. Sometimes gross renal vein invasion is seen. The prototypic collecting duct carcinoma has a tubular or tubulopapillary growth pattern in which irregular angulated glands infiltrate renal parenchyma and are associated with a desmoplastic stroma {775. The edge of the tumour is often ill-defined and there is extensive permeation of renal parenchyma. Epidemiology Collecting duct carcinoma is rare. Metastases to bone are often osteoblastic. Macroscopy Collecting duct carcinomas are usually located in the central region of the kidney. about 5 cm) and they typical- one of exclusion.R. Clinical features Patients with collecting duct carcinoma usually present with abdominal pain.2470}. Small papillary infoldings and micro- A B Fig. Tumour spread and staging Collecting duct carcinomas often display infiltration of perirenal and renal sinus fat. A Medullary location of the tumour. Areas of necrosis and satellite nodules may be present. Criteria for diagnosing collecting duct carcinoma have been proposed {2470}. Srigley H. Metastases to regional lymph nodes.5 to 12 cm (mean. Bellini duct carcinoma. While most collecting duct carcinomas are located centrally in the medullary zone.39 Carcinoma of the collecting ducts of Bellini.1298. C Higher magnification discloses small papillary infoldings to the tubular lumina. liver. Over 100 cases have been described and there is a wide age range from 13-83 years (mean. flank mass and haematuria.40 Carcinoma of the collecting ducts of Bellini.

fibrous stalks and desmoplastic stroma .Reactive with antibodies to high molecular weight cytokeratin . broad stalks containing inflamed fibrous stroma. High density mapping of the entire long arm of chromosome 1 showed that the region of minimal deletion is located at 1q32.Location in a medullary pyramid (small tumours) .05 Diagnostic criteria for collecting duct carcinoma. and 21q {2094}. cordlike patterns and sarcomatoid features may be encountered. About twothirds of patients die of their disease within two years of diagnosis {2470}.1-32. In contrast to clear cell RCC. Table 1.41 Carcinoma of the collecting ducts of Bellini.Central location (large tumours) . Prognosis and predictive factors The typical collecting duct carcinomas have a poor prognosis with many being metastatic at presentation. The most frequent ones have a predominantly papillary growth pattern but they differ from usual papillary carcinoma by a lack of circumscription. LOH was identified on multiple chromosomal arms in CDC. CK19) are commonly present and co-expression of vimentin may be seen {2470}. Lectin histochemistry. The sarcomatoid change is a pattern of dedifferentiation similar to that seen in other types of renal carcinoma {153}. The cells of collecting duct carcinoma usually display high grade (Fuhrman 3 and 4) nuclear features. 6p. extrarenal. including 1q. One study suggested that 8p LOH might be associated with high tumour stage and poor patient prognosis {2335}.Inflammatory desmoplastic stroma with numerous granulocytes . Major Criteria . Glycogen is usually inconspicuous in collecting duct carcinoma. and lymphatic and venous infiltration . high nuclear grade and sometimes an association with more typical tubular patterns of collecting duct carcinoma elsewhere {2470}. The CD10 and villin stains are negative. Solid.Intra tubular epithelial atypia adjacent to the tumour Immunoprofile Tumour cells usually display positivity for low molecular weight and broad spectrum keratins.C Note high grade cytological atypia.Absence of urothelial carcinoma Minor Criteria . adenocarcinoma or urothelial carcinoma with glandular dif- ferentiation arising in renal pelvis and metastatic adenocarcinoma {2470}.Reactive with Ulex europaeus agglutinin lectin . Both intraluminal and intracytoplasmic mucin may be seen. There is variable immunostaining for CD15 and epithelial membrane antigen. HER2/neu amplifications have been described in CDCs {2357}. usual Ulex europaeus agglutinin-1 and peanut lectin are commonly positive. B.Extensive renal.Typical histology with irregular tubular architecture and high nuclear grade . Some tumours with other morphologies have been proposed as collecting duct carcinomas. Somatic genetics Molecular events that contribute to the development of collecting duct carcinomas (CDCs) are poorly understood because only few cases have been analyzed.2 {2501}. The cells may have a hobnail pattern of growth and the cytoplasm is generally eosinophilic. A Tubulopapillary type of growth.990}. Differential diagnosis The main differential diagnoses of collecting duct carcinoma include papillary renal cell carcinoma. 1. although dysplasia may be seen in collecting ducts adjacent to other types of renal carcinoma.Papillary architecture with wide. The central location and associated tubular epithelial dysplasia (atypia) are helpful in supporting a diagnosis.cystic change may be seen. 8p. desmoplasia. 13q. High molecular weight keratins (34βE12. Loss of chromosomal arm 3p can be found in CDC {674. A B C Fig. 34 Tumours of the kidney .

Clinical features Signs and symptoms With few exceptions these are seen in young people with sickle cell trait between ages 10 and 40 (mean age 22 years) and chiefly in males by 2:1. Metastatic deposits such as cervical nodes or brain tumour may be the initial evidence of disease {2119}. The cells are Fig. 1. Over a period of 22 years the Armed Forces Institute of Pathology had collected only 34 cases {562} and over the next 5 years only 15 more had been described {1304}. Caliectasis without pelviectasis and tumour encasing the pelvis are also described. The sheets of cells can have squamoid or rhabdoid quality. Renal medullary carcinoma 35 . A Adenoid cystic morphology. Oedematous or collagenous stroma forms a considerable bulk of many Epidemiology This is a rare tumour. A reticular growth pattern and a more compact adenoid cystic morphology are the common features. ICD-O code 8319/3 eosinophilic with clear nuclei and usually with prominent nucleoli.44 Renal medullary carcinoma. Neutrophils are often admixed with the tumour and the advancing margins often bounded by lymphocytes.J. Note sickled red cells at lower left. The common symptoms are gross haematuria and flank or abdominal pain. Size ranges from 4 to 12 cm with a mean of 7 cm. Imaging In the clinical setting of a young person with sickle cell trait it is often possible to anticipate the correct diagnosis with imaging studies {557. are typical. 1.1304}. Davis Definition A rapidly growing tumour of the renal medulla associated almost exclusively with sickle cell trait. Note lymphocytes at advancing margin. invading renal sinus. 1. Infiltrating tumour expanding renal contour. Histopathology Most cases have poorly differentiated areas consisting of sheets of cells.43 Renal medullary carcinoma. B C Fig.42 Renal medullary carcinoma. Weight loss and palpable mass are also common. Most show much haemorrhage and necrosis {562}.Renal medullary carcinoma C. Centrally located tumours with an infiltrative growth pattern. C Poorly differentiated area. Infiltrating tumour with perinephric extension at lower right. B Adenoid cystic area admixed with neutrophils. Fig. Macroscopy These are poorly circumscribed tumours arising centrally in the kidney.

CEA is usually positive. this and radiotherapy has not altered the course of the disease {1304}. These tumours are now widely regarded as a more aggressive variant of the collecting duct carcinoma {648.2470}. 36 Tumours of the kidney .tumours. A majority of cases show droplets of cytoplasmic mucin and sickled erythrocytes {562}. Chemotherapy has been known to prolong survival by a few months Immunoprofile Keratin AE1/AE3 is nearly always positive as is EMA but typically less strongly so.2) but negative high molecular weight cytokeratin {2220}. liver and lungs most often involved. One study found strong expression of low molecular {2084} but generally. Metastases are both lymphatic and vascular with lymph nodes. weight cytokeratin (CAM 5. Prognosis and predictive factors The prognosis is poor and the mean duration of life after surgery has been 15 weeks.

while both the t(X.2-associated carcinomas most closely resemble clear cell renal carcinomas. Somatic genetics These carcinomas are defined by several different translocations involving chromosome Xp11. TFE3 is a member of the basic-helixloop-helix family of transcription factors. Only about 50% express epithelial markers such as cytokeratin and EMA by immunohistochemistry {108. unpublished observations). Macroscopy Renal carcinomas associated with Xp11.1)(p11. The ASPL-TFE3 carcinomas characteristically present at advanced stage {109}.q25) Fig. fewer hyaline nodules. Occasional PRCCTFE3 renal carcinomas have demonstrated distinctive intracisternal microtubules identical to those seen in extraskeletal myxoid chondrosarcoma {108}. Ultrastructure Ultrastructurally. The PRCC-TFE3 renal carcinomas generally feature less abundant cytoplasm. The expression levels of TFE3 fusion proteins appear aberrantly high compared to native TFE3 {113}.C) Renal carcinomas associated with Xp11. Most of the ASPLTFE3 renal carcinomas also demonstrate membrane-bound cytoplasmic granules and a few contain membrane-bound rhomboidal crystals identical to those seen in soft tissue alveolar soft part sarcoma (ASPS) {109}. and can act as aberrant transcription factors {2432.2809}.17) renal A B C Fig. fewer psammoma bodies. The tumours consistently label for the Renal Cell Carcinoma Marker antigen and CD10.2 translocations / TFE3 gene fusions Definition These carcinomas are defined by several different translocations involving chromosome Xp11. perhaps because the fusion partners of TFE3 are ubiquitously expressed and contribute their promoters to the fusion proteins. all resulting in gene fusions involving the TFE3 gene. which results in fusion of the PRCC and TFE3 genes. discrete cell borders.q21) {1710}. vesicular chromatin and prominent nucleoli.B. Histopathology The most distinctive histopathologic appearance is that of a carcinoma with papillary architecture comprised of clear cells.q12). the t(X.46 t(X:17) renal carcinoma. which results in fusion of the ASPL (also known as RCC17 or ASPSCR1) and TFE3 genes {109. Both the PRCC-TFE3 and ASPL-TFE3 fusion proteins retain the TFE3 DNA binding domain. 1. all resulting in gene fusions involving the TFE3 gene. though a few older patients have been reported {108}. localize to the nucleus. (A. {371. Ladanyi Immunoprofile The most distinctive immunohistochemical feature of these tumours is nuclear immunoreactivity for TFE3 protein {113}. resulting in fusion of the PSF and TFE3 genes.1055.17)(p11.2 translocations are most commonly tan-yellow.2 translocations / TFE3 gene fusions 37 .p34). and a more nested.1)(p11. Xp11. Note sheet like growth pattern and clear cells. P. and often feature cells with granular eosinophilic cytoplasm.2.2. Interestingly. Argani M. 1. these tumours frequently have a more nested architecture. and the inv(X)(p11.45 t(X:17) renal carcinoma. and the labeling is often focal.2. compact architecture {108}. and (M.1056. The ASPL-TFE3 renal carcinomas are characterized by cells with voluminous clear to eosinophilic cytoplasm. Ladanyi.2.2626}.1424}. These include the t(X.2. often arising within characteristic hyaline nodules {109}. Psammoma bodies are constant and sometimes extensive.109}. and often necrotic and haemorrhagic.1084. however.Renal carcinomas associated with Xp11. Clinical features These carcinomas predominantly affect children and young adults. resulting in fusion of the NonO (p54nrb) and TFE3 genes {471}. hyaline nodules and psammoma bodies. Note papillary architecture. the t(X.

A B C D Fig.17)(p11. Partial karyotypes showing t(X.e.48 Xp 11. Suresh C.47 A t(X:1) RCC.q25.q21) in a renal tumour from a male (courtesy of Dr.2. Reprinted and adapted with permission from P. 1. Argani et al. Note tubular and papillary architecture. D t(X:1) RCC. {109}. Note papillary architecture with foam cells. the t(X. the derivative X chromosome is not seen in ASPS) {109}. 38 Tumours of the kidney . carcinomas and the soft tissue ASPS contain identical ASPL-TFE3 fusion transcripts. Note alveolar growth pattern and clear cells.1)(p11. Note strong nuclear labeling of the tumour cells.3) in a renal tumour from a female. their clinical course thus far appears to be indolent. Fig. 1. The positions of the breakpoints are indicated by arrows (standard G-banding). Prognosis and predictive factors Very little is known about the clinical behaviour of these carcinomas.49 Xp11 translocation carcinomas.2. Fig. Note compact nested architecture.2-translocation renal carcinoma. B t(X:17) renal carcinoma. C t(X:1) RCC.17) translocation is consistently balanced (reciprocal) in the former but usually unbalanced in the latter (i. While the ASPL-TFE3 renal carcinomas usually present at advanced stage. Jhanwar) and a t(X. 1. TFE3 protein expression.

and 19. A B Fig. and a second patient developed RCC and neuroblastoma simultaneously {1380.J. in 12 cases. vimentin and keratins 8. Microsatellite analysis using polymorphic markers in three tumours showed allelic imbalances involving a number of loci. A familial genetic susceptibility syndrome may be involved. Median tumour size.1694. and 20 and are negative for keratins 7.5 years (range. Some tumours are characterized by solid and papillary architecture. B Tumour composed of large cells with finely and coarsely granular eosinophilic cytoplasm. {1281. 1694}.Renal cell carcinoma associated with neuroblastoma L. Histopathology These tumours are morphologically heterogeneous {1380}.1380. 2 to 35). Males and females are equally affected. The architecture is papillary and there is a psammoma body. B Higher magnification showing nuclei of variable size.1394. Renal cell carcinoma associated with neuroblastoma 39 . Clinical features Eighteen cases have been reported.08 cm).1694}. was 4 cm (range.1380. Tumour spread and staging Five patients developed metastases involving the liver. Etiology Therapy for neuroblastoma may play a role in the pathogenesis of subsequent RCC.2743}.2743}.2743}. one patient was not treated for stage IVS neuroblastoma.1694.51 Carcinoma associated with neuroblastoma. A B Fig. 1. Prognosis and predictive factors Prognosis correlates with tumour stage and the presence of high grade nuclear atypia. clear cell renal cell carcinomas that were detected incidentally. There is focal papillary architecture. 1. Macroscopy Either kidney may be involved and four cases were bilateral. most often 20q13 {1281. similar to other histologic types of RCC. Age was <2 years at time of diagnosis of neuroblastoma. In a second group. cells with abundant eosinophilic cytoplasm with a lesser number of cells with reticular cytoplasm.1694. Immunoprofile These tumours are usually positive for EMA. Somatic genetics Cytogenetic analysis of two tumours showed deletions of multiple chromosomal loci {2743}. lymph nodes. 1. 14.50 Carcinoma associated with neuroblastoma. thyroid and adrenal glands. often with nucleoli of medium size. However. 18.1489. and bone {1394. Median age at time of diagnosis of RCC was 13. Medeiros Definition Renal cell carcinoma associated with neuroblastoma occurs in long-term survivors of childhood neuroblastoma. the tumours are small. Some are vacuolated. A Conspicuous variability in nuclear size and shape. and mild to moderate atypia {1281. A Note a mixture of areas of compact growth resembling renal oncocytoma and areas of papillary growth.

desmosomes. Clinical features They usually present as asymptomatic masses. These tumours show extensive positivity for Ulex europaeus. 6. there is a characteristic A Immunoprofile These tumours have a complex immunophenotype and stain for a wide variety of cytokeratins including low molecular weight keratins (CAM 5. combination of chromosome losses. Many of these tumours had been previously diagnosed as unclassified or spindle cell (sarcomatoid) carcinomas. Prognosis and predictive factors The prognosis sems to be favourable. foam cell deposits and chronic inflammation may be present. often found on ultrasound. Occasionally.R. The parallel tubular arrays often have a spindle cell configuration sometimes simulating leiomyoma or sarcoma. peanut and soya bean agglutinins. Epidemiology There is a wide age range of 17-82 (mean 53) years and a male to female ratio of 1:4 {2024. Occasionally. small. Markers of proximal nephron such as CD10 and B C Fig. 4. CK18. they are composed of tightly packed. Individual cells are small with cuboidal or oval shapes and low-grade nuclear features. Srigley Definition Low-grade polymorphic renal epithelial neoplasms with mucinous tubular and spindle cell features.52 A. microvillous borders. CK19 and 34βE12 {2469}. villin are generally absent. mucinous tubular and spindle cell carcinomas. MAK 6). 8. luminal borders and occasional tonofilaments {2469}. generally involving chromosome 1.Mucinous tubular and spindle cell carcinoma J.2469}. C Mucinous tubular and spindle cell carconoma composed of spindle cells and cuboidal cells forming cords and tubules. The mucinous stroma is highlighted with stains for acid mucins.2. 1. they may present with flank pain or hematuria. elongated tubules separated by pale mucinous stroma. are well circumscribed and have grey or light tan. 16 and 17 {2137. Histopathology Histologically. CK7. Epithelial membrane antigen is commonly present. Somatic genetics Using comparative genomic hybridization and FISH. 13 and 14 and gains of chromosome 7.2469}. Note basophilic extracellular mucin. only one example has been reported with metastasis and this tumour is best considered as a low-grade carcinoma {2471}. 40 Tumours of the kidney . and vimentin and CD15 staining may be seen. Ultrastructure The spindle cells show epithelial features like tight junctions. uniform cut surfaces. 11. B. Macroscopy Macroscopically. areas of necrosis.

Somatic genetics Loss of the Y chromosome and a combined trisomy of chromosome 7 and 17 are the first visible karyotype aberrations in papillary renal tumours. papillary adenomas are solitary. B Papillary adenoma composed of complex branching papillae on partially hyalinized stromal cores. yellow to greyish white nodules as small as less than 1 mm in diameter in the renal cortex. amphophilic to basophilic. resembling type 2 papillary renal cell carcinoma. Eble H. it is not possible to distinguish adenomas and carcinomas by genetic changes.53 Multiple renal papillary adenomas. as are foamy macrophages {2161}. be a result of the lower number of genetic alterations per tumour. Less frequently. 1. which change their biological behaviour {1369}. Similar lesions frequently develop in patients on long-term hemodialysis and occur in 33% of patients with acquired renal cystic disease {1143}. Mitotic figures usually are absent. Macroscopy Papillary adenomas are well circumscribed.2163. Moch Definition Papillary adenomas are tumours with papillary or tubular architecture of low nuclear grade and 5 mm in diameter or smaller. Small renal tumours demonstrate similar. 2854}. The clinically indolent course of small papillary tumours may. or tubulopapillary architectures corresponding closely to types 1 and 2 papillary renal cell carcinoma {585}. 1.N. in part. A B Fig. When they are very numerous. papillary. These data suggest that initiating genetic events for papillary renal adenomas include gains of chromosome 7 and loss of a sex chromosome. The cells have round to oval nuclei with stippled to clumped chromatin and inconspicuous nucleoli. aquire additional genetic alterations during growth. but less extensive genetic alterations than their papillary renal carcinoma counterparts. In most. These type 1 adenomas have complex papillae covered by a single layer of small epithelial cells with inconspicuous cytoplasm. but larger ones sometimes are roughly conical with a wedgeshaped appearance in sections cut at right angles to the cortical surface. Mucinous tubular and spindle cell carcinoma / Papillary adenoma of the kidney 41 . Most occur just below the renal capsule.54 Papillary adenoma. the cytoplasm is scant and pale. but occasionally they are multiple and bi- Fig. the cytoplasm is voluminous and eosinophilic. However. A Two papillary adenomas in the renal cortex. nuclear grooves may be present. This combination of genetic alterations has been found as the sole karyotype change in small papillary renal tumours from 2 mm to 5 mm in diameter. Based on these findings. ICD-O code 8260/0 lateral. Psammoma bodies are common.Papillary adenoma of the kidney J. Histopathology Papillary adenomas have tubular. this has been called "renal adenomatosis". The smallest ones usually are spherical. because many carcinomas show only few genetic alterations. Autopsy studies have found papillary adenomas increase in frequency in adulthood from 10% of patients younger than 40 years to 40% in patients older than 70 years {653. Some have thin fibrous pseudocapsules. Usually. all with nuclear grade 1 {1373}. it has been suggested that papillary adenomas Clinical features Papillary adenomas are the most common neoplasms of the epithelium of the renal tubules. One CGH analysis studied 6 papillary tumours less than 6 mm in diameter and observed gain of chromosome 7 in 4 specimens {2107}.

flank pain.55 Oncocytoma. Moch Definition Oncocytoma is a benign renal epithelial neoplasm composed of large cells with mitochondria-rich eosinophilic cytoplasm. A few small foci of necroses do not exclude an oncocytoma. 2945}. Haemorrhage is present in up to 20% of cases but grossly visible necrosis is extremely rare {77. 1.J. Clinical features Signs and symptoms The majority is asymptomatic at presentation with discovery occurring during radiographic work-up of unrelated conditions. they may be filled with red blood cells. A central. Atypical mitotic figures are not seen.2050}.2178. C Renal oncocytoma. Histopathology Characteristically. nonencapsulated neoplasms that are classically mahogany-brown and less often tan to pale yellow. tubules. or microcysts.1060. Often there is a hypocellularhyalinized stroma. Most occur sporadically. Epidemiology First described by Zippel in 1942 {2939} and later by Klein and Valensi {1335}. Males are affected nearly twice as often as females. Reuter C. A smaller population of cells with scanty granular cytoplasm.1497. and a centrally placed nucleolus. acini. Note clonal variation. ICD-O code 8290/0 dence in the seventh decade of life. Isolated foci of clear cell change may be present in areas of stromal hyalinizations.563. 1. round and regular nuclei with evenly dispersed chromatin. Note rounded aggregates of small. B Renal oncocytoma. or a palpable mass. Occasional clusters of cells with pleomorphic and hyperchromatic nuclei are common.812. stellate scar may be seen in up to 33% of cases but is more commonly seen in larger tumours. and dark hyperchromatic nuclei may also be observed.Oncocytoma V. The predominant cell type (so-called "oncocyte") is round-topolygonal with densely granular eosinophilic cytoplasm. While small papillae may very rarely be seen focally.1094}.1174. Few patients present with hematuria. these tumours have solid compact nests.2050.563. A rare oncocytoma may have one or two mitotic figures in the sections examined. eosinophilic cells. 607. If microcysts are present. Imaging The diagnosis of oncocytoma may be suggested by computed tomography or magnetic resonance imaging in tumours featuring a central scar {558. a high nuclear: cytoplasmic ratio. oncocytoma comprises approximately 5% of all neoplasms of renal tubular epithelium in surgical series {77. Most series show a wide age distribution at presentation with a peak inci- Fig.56 A Oncocytoma. pure or extensive papillary architecture is not a feature A B C Fig. Cells at left have more cytoplasm than on the right. Davis H.453. Macroscopy Oncocytomas are well-circumscribed.E. 42 Tumours of the kidney . thought to arise from intercalated cells.

of this tumour. In surgical series. though pleomorphic forms are rarely seen {722. renal oncocytoma is characterized by cells containing numerous mitochondria. but rather as a manifestation of high grade carcinoma of the type from which it arose. unclassified is a diagnostic category to which renal carcinomas should be assigned when they do not fit readily into one of the other categories {1370. Occasionally.826. unclassified 43 .563. {1181. mixtures of epithelial and stromal elements. Since oncocytomas are benign neoplasms. oncocytic change in benign tubules. Since this category must contain tumours with varied appearances and genetic lesions.2108. this group often amounts to 4-5% of cases.2108}. grading is not performed. the majority of which are of normal size and shape. The oncocytic nodules usually have the morphologic and ultrastructural features of oncocytoma although some may have either chromophobe or hybrid features. Notably absent are the microvesicles typical of chromophobe tumours. and unrecognizable cell types. Somatic genetics Most renal oncocytomas display a mixed population of cells with normal and abnormal karyotypes {1376.2687}.2050}. Microscopic extension into perinephric adipose tissue may be seen infrequently {1584} and vascular invasion has been described {77. translocation of t(5. Since there is no evidence that renal tumours arise de novo as sarcomatoid carcinomas. Prognosis and predictive factors Renal oncocytomas are benign neoplasms. mucin production. which might place a carcinoma in this category include: apparent composites of recognized types. Some of the cases show loss of chromosome 1 and 14 {1079. Sarcomatoid change has been found to arise in all of the types of carcinoma in the classification. In a few oncocytomas.1378}.563}. Oncocytoma / Renal cell carcinoma. microcysts lined by oncocytic cells and clusters of oncocytes within the renal interstitium Ultrastructure Through ultrastructural examination. Other cytoplasmic organelles are sparse and unremarkable. such tumours are appropriately assigned to renal cell carcinoma. examples of fea- tures. unclassified J. including oncocytic tumours.2618. as well as in urothelial carcinoma of the renal pelvic mucosa. unclassified.1376. Oncocytosis (Oncocytomatosis) Several cases have been reported in which the kidneys have contained a large number of oncocytic lesions with a spectrum of morphologic features.2617}. However.2514}.q13) was detected {513. it is not viewed as a type of its own. it cannot be defined in a limiting way. Renal cell carcinoma. There is no diffuse cytoplasmic Hale’s colloidal iron staining in oncocytomas. Eble ICD-O code 8312/3 Renal cell carcinoma.11)(q35. sarcomatoid morphology without recognizable epithelial elements.N.2782}. This conclusion is based largely on the data from several recent studies including rigorous pathologic review and adequate clinical follow-up in which not a single case of oncocytoma resulted in the death of a patient due to metastatic disease {77. the sarcomatoid elements overgrow the antecedent carcinoma to the extent that it cannot be recognized.

Foci of haemorrhage and necrosis are common. The cut surfaces vary from grey to tan to yellow and may be soft or firm. Multifocality is uncommon. The cytoplasm is scant and pale or light pink. some have been incidental findings. uniform nuclei and absent or inconspicuous nucleoli. Patients with metanephric adenofibroma have ranged from 5 months to 36 years (median = 30 months) {120}. 1. round acini with an embryonal appearance. Hyalinized scar and focal osseous metaplasia of the stroma are present in 1020% of tumours {561}.58 Metanephric adenoma. Arroyo et al. these patients have had no progression. Other than one patient with regional metastases from the carcinoma. The cells of metanephric adenoma are monotonous. uniform. 1. 8325/0 9013/0 8933/3 Epidemiology Metanephric adenoma occurs in children and adults. with small. or hematuria.N. Grignon H. Eble D. Approximately 50% of tumours contain papillary structures. B Complicated ductal architecture with psammoma bodies. Metanephric adenofibroma is a compos- A B Fig. The nuclei are only a little larger than those of lymphocytes and are round or oval with delicate chromatin.and small cysts in 10% {561.57 Metanephric adenoma. A single case of high grade sarcoma arising in association with metanephric adenoma (metanephric adenosarcoma) has been reported {2072}. at low magnification this pattern may be mistaken for a solid sheet of cells. Clinical features Approximately 50% of metanephric adenoma are incidental findings with others presenting with polycythemia. Metanephric adenofibromas are typically solitary tan partially cystic masses with indistinct borders {120}. Mitotic figures are absent or rare. most commonly in the fifth and sixth decades.J. abdominal or flank pain. A Well circumscribed tumour without encapsulation. The stroma ranges from inconspicuous to a loose oedematous stroma. ICD-O codes Metanephric adenoma Metanephric adenofibroma Metanephric adenosarcoma Wilms tumour or carcinoma occurred in association with metanephric adenofibroma. The tumours are typically well circumscribed but not encapsulated. Since the acini and their lumens are small.Metanephric adenoma and metanephric adenofibroma J. calcification is present in approximately 20%. Histopathology Metanephric adenoma is a highly cellular tumour composed of tightly packed small. Moch Definition Metanephric adenoma is a highly cellular epithelial tumour composed of small. Long branching and angulated tubular structures also are common. There is a 2:1 female preponderance {561}.1237}. Macroscopy Metanephric adenomas range widely in size. Presenting symptoms of metanephric adenofibroma have included polycythemia or hematuria. {120} described several cases in which either Fig. uniform. embryonic-appearing cells. 44 Tumours of the kidney . Psammoma bodies are common and sometimes numerous. usually consisting of tiny cysts into which protrude blunt papillae reminiscent of immature glomeruli. most have been 30 to 60 mm in diameter {561}. The junction with the kidney is usually sharp and without a pseudocapsule. mass. There is a 2:1 ratio of males to females.

Psammoma bodies are common and may be numerous. Variable amounts of hyalinization and myxoid change are present. ite tumour in which nodules of epithelium identical to metanephric adenoma are embedded in sheets of moderately cellular spindle cells.926. Metanephric adenoma and metanephric adenofibroma 45 .2171. tubules and papillary structures. as described above in metanephric adenoma. and adipose differentiation occur occasionally. The relative amounts of the spindle cell and epithelial components vary from predominance of spindle cells to a minor component of spindle cells. 1.60 Metanephric adenoma. and have inconspicuous nucleoli. Nucleoli are inconspicuous and a few mitotic figures are present in a minority of cases. A deletion at chromosome 2p as the only genetic abnormality was described in 1 tumour {2522} and a tumour suppressor gene region on chromosome 2p13 was delineated {2058}. Epithelial membrane antigen and cytokeratin 7 are frequently negative and CD57 is positive. A Metanephric adenoma composed of tightly packed small acini lined by uniform small cells with inconspicuous cytoplasm. ovoid. as have positive reactions with antibody to vimentin {951}. Positive intranuclear reactions with antibody to WT-1 are common in metanephric adenoma {1824}. 1. Somatic genetics Cytogenetic analysis of metanephric adenoma revealed normal karyotypes in 5 cases and normal copy numbers of chromosomes 7 and 17 were seen by FISH in 2 cases {840. Their cytoplasm is eosinophilic but pale and the nuclei are oval or fusiform.59 Metanephric adenoma. The spindle cell component consists of fibroblast-like cells.1237. A Metanephric adenoma with numerous psammoma bodies. Angiodysplasia and glial. The reactions of the adenomatous elements are similar to those reported for metanephric adenoma. B The nuclei are uniform. Positive reactions with a variety of antibodies to cytokeratins have been reported. B Multiple small tubules composed of a monotonous population of cuboidal cells. The border of the tumour with the kidney is typically irregular and the spindle cell component may entrap renal structures as it advances. Immunoprofile Immunohistochemical studies of metanephric adenoma have given variable results. A B Fig. The stroma of metanephric adenofibroma frequently reacts with antibody to CD34 {120}. 2652}. The epithelial component consists of small acini. cartilaginous.A B Fig.

Fig. which is identical to the stromal component of metanephric adenofibroma {110. and thin. indistinct cytoplasmic extensions. ICD-O code 8935/1 diameter is 5 cm.Fig. Many of the characteristic features of MST result from its interaction with entrapped native renal elements. 1. lobulated fibrous mass centred in the renal medulla. and stromal component which is identical to metanephric stromal tumour (top). 1. less myxoid spindle cell areas at the periphery of these collarettes yield nodular variations in cellularity. Histopathology MST is an unencapsulated but subtly infiltrative tumour of spindled to stellate cells featuring thin. hyperchromatic nuclei. such angiodysplasia Clinical features Metanephric stromal tumour (MST) is approximately one-tenth as common as congenital mesoblastic nephroma {110. MST characteristically surrounds and entraps renal tubules and blood vessels to form concentric "onionskin" rings or collarettes around these structures in a myxoid background. Note the nodular appearance. Mean age at diagnosis is 24 months. Argani Definition Metanephric stromal tumour is a rare benign paediatric renal neoplasm. Rarely. 1. The typical presentation is that of an abdominal mass.1075}. 120}. Approximately one-half of cases are grossly cystic. Mean Fig. Note epithelial area which is identical to metanephric adenoma (bottom).62 Metanephric stromal tumour. Macroscopy MST is typically a tan.63 Metanephric stromal tumour. while onesixth are multifocal. A rare adult tumour has been identified {255}. though haematuria is not uncommon and rare patients may present with manifestations of extra-renal vasculopathy such as hypertension or haemorrhage. consisting of epithelioid transformation of medial smooth muscle and myxoid change.61 Metanephric adenofibroma. Most tumours induce angiodysplasia of entrapped arterioles. Metanephric stromal tumour P. 46 Tumours of the kidney . More cellular. Note juxtaglomerular cell hyperplasia.

results in intratumoral aneurysms.65 Metanephric stromal tumour. Rare patients have suffered morbidity or mortality from the manifestations of extra renal angiodysplasia. 1. though heterologous glial areas label for GFAP and S-100 protein. predominantly away from entrapped tubules. B Note positivity for GFAP in glial foci. Necrosis is unusual.66 Metanephric stromal tumour. A Glial-epithelial complexes. A B Fig. but labeling may be patchy. 1. apparently induced by MST. which may occasionally lead to hypertension associated with hyperreninism. Onefourth of MSTs feature juxtaglomerular cell hyperplasia within entrapped glomeruli. A B Fig. B CD34 positivity of spindle cells. and vascular invasion is absent in MST. 47 . A B Metanephric stromal tumour Fig. Desmin. One-fifth of MSTs demonstrate heterologous differentiation in the form of glia or cartilage.64 Metanephric stromal tumour. cytokeratins. A Note spindled and epithelioid stromal cells and (B) striking angioplasia. Excision is adequate therapy. Immunoprofile MSTs are typically immunoreactive for CD34. and S-100 protein are negative. with no reports of metastases or even local recurrence as of this writing. Prognosis and predictive factors All identified MSTs have had a benign course. 1. A Angiodysplasia and concentric perivascular growth.

Nephroblastoma

E.J. Perlman J.L. Grosfeld K. Togashi L. Boccon-Gibod

Definition Nephroblastoma is a malignant embryonal neoplasm derived from nephrogenic blastemal cells that both replicates the histology of developing kidneys and often shows divergent patterns of differentiation. ICD-O code Synonym Wilms tumour. Epidemiology Nephroblastoma affects approximately one in every 8,000 children {317}. There is no striking sex predilection and tumours occur with equal frequency in both kidneys. The mean age at diagnosis is 37 and 43 months for males and females, respectively, and 98 percent of cases occur in individuals under 10 years of age, although presentation in adulthood has been reported {315,959, 1148}. 8960/3

The stable incidence of nephroblastoma in all geographic regions suggests that environmental factors do not play a major role in its development. The variation in incidence among different racial groups, however, indicates a genetic predisposition for this tumour is likely: the general risk is higher among African-Americans and lower among Asians. Clinical features Nephroblastoma most commonly comes to clinical attention due to the detection of an abdominal mass by a parent when bathing or clothing a child. Abdominal pain, hematuria, hypertension, and acute abdominal crisis secondary to traumatic rupture are also common. More rare presentations include anaemia, hypertension due to increased renin production, and polycythemia due to tumoural erythropoietin production {959,2087}. The majority of nephroblastomas are treated using therapeutic protocols created by either the International Society of Paediatric Oncology (SIOP) or the Children’s Oncology Group (COG). The SIOP protocols advocate preoperative therapy followed by surgical removal. This approach allows for tumour shrinkage prior to resection, yielding a greater frequency and ease of complete resectability. Continued therapy is then determined by the histologic evidence of responsiveness to therapy, as indicated by post-therapy classification. The COG (including the prior National Wilms Tumour Study Group) has long advocated primary resection of tumours, followed by therapy that is determined by stage and classification into "favourable" and "unfavourable" histology categories. This allows for greater diagnostic confidence and greater ability to stratify patients according to pathologic and biologic parameters. While the SIOP and COG protocols have intrinsically different philosophies regarding therapy, they have resulted in similar outcomes.

Imaging Nephroblastoma typically manifests as a solid mass of heterogeneous appearance that distorts the renal parenchyma and collecting system. The lesion can be associated with foci of calcification. Isolated nephrogenic rests tend to appear as homogeneous nodules {1567}.
Macroscopy Most nephroblastomas are unicentric. However, multicentric masses in a single kidney and bilateral primary lesions have been observed in 7 and 5 percent of cases, respectively {492,2381,2820}. Nephroblastomas are usually solitary rounded masses sharply demarcated from the adjacent renal parenchyma by a
Table 1.06 Revised SIOP Working Nephroblastoma. A. For pretreated cases I. Low risk tumours Cystic partially differentiated nephroblastoma Completely necrotic nephroblastoma II. Intermediate risk tumours Nephroblastoma – epithelial type Nephroblastoma – stromal type Nephroblastoma – mixed type Nephroblastoma – regressive type Nephroblastoma – focal anaplasia III. High risk tumours Nephroblastoma – blastemal type Nephroblastoma – diffuse anaplasia B. For Primary nephrectomy cases I. Low risk tumours Cystic partially differentiated nephroblastoma II. Intermediate risk tumours Non-anaplastic nephroblastoma and its variants Nephroblastoma-focal anaplasia III. High risk tumours Nephroblastoma – diffuse anaplasia

Classification

of

Fig. 1.67 Aniridia in a child, associated with nephroblastoma.

48

Tumours of the kidney

peritumoural fibrous pseudocapsule. Lesions most commonly have a uniform, pale grey or tan appearance and a soft consistency, although they may appear firm and whorled if a large fraction of the lesion is composed of mature stromal elements. Polypoid protrusions of tumour into the pelvicaliceal system may occur resulting in a "botryoid" appearance {1602}. Cysts may be prominent. Rarely, nephroblastoma occurs in extrarenal sites {28,1976}. Tumour spread and metastasis Nephroblastomas generally have a restricted pattern of metastasis, most commonly regional lymph nodes, lungs, and liver

A

B

Fig. 1.68 Nephroblastoma. A circumscribed, encapsulated lesion with cyst formation. B Polypoid extension into renal pelvis.

{318}. Metastatic sites other than these (i.e., bone or brain) are unusual and should suggest alternative diagnoses.

Table 1.07 Staging of paediatric renal tumours: Children’s Oncology Group (COG) and Societé International d’Oncology Paediatrique / International Society of Paediatric Oncology (SIOP). Stage I Definition COG: SIOP:

Limited to kidney and completely resected. Renal capsule is intact. Limited to kidney or surrounded with fibrous pseudocapsule if outside the normal contours of the kidney. Presence of necrotic tumour or chemotherapy-induced changes in the renal sinus or soft tissue outside the kidney does not upstage the tumour in the post-therapy kidney.

Staging The most widely accepted staging systems for nephroblastomas rely on the identification of penetration of the renal capsule, involvement of renal sinus vessels, positive surgical margins, and positive regional lymph nodes; there are minor differences between the staging systems utilized by the SIOP and COG. While bilateral nephroblastomas are designated as stage V, their prognosis is determined by the stage of the most advanced tumour and by the presence or absence of anaplasia. Histopathology Nephroblastomas contain undifferentiated blastemal cells and cells differentiating to various degrees and in different proportions toward epithelial and stromal lineages. Triphasic patterns are the most characteristic, but biphasic and monophasic lesions are often observed. While most of these components represent stages in normal or abnormal nephrogenesis, non renal elements, such as skeletal muscle and cartilage occur {193}. The blastemal cells are small, closely packed, and mitotically active rounded or oval cells with scant cytoplasm, and overlapping nuclei containing evenly distributed, slightly coarse chromatin, and small nucleoli. Blastemal cells occur in several distinctive patterns. The diffuse blastemal pattern is characterized by a lack of cellular cohesiveness and an aggressive pattern of invasion into adjacent connective tissues and vessels, in contrast to the typical circumscribed, encapsulated, and "pushing" border characteristic of most nephroblastomas. Other blastemal patterns tend to be cohesive. The nodular and serpentine blastemal patterns are characterized by round or undulating, sharply defined cords or nests of blastemal cells set in a Nephroblastoma

COG & SIOP: Renal sinus soft tissue may be minimally infiltrated, without any involvement of the sinus vessels. The tumour may protrude into the pelvic system without infiltrating the wall of the ureter. Intrarenal vessels may be involved. Fine needle aspiration does not upstage the tumour. II COG & SIOP: Tumour infiltrates beyond kidney, but is completely resected. Tumour penetration of renal capsule or infiltration of vessels within the renal sinus (including the intrarenal extension of the sinus). Tumour infiltrates adjacent organs or vena cava but is completely resected. Includes tumours with prior open or large core needle biopsies. May include tumours with local tumour spillage confined to flank. COG & SIOP: Gross or microscopic residual tumour confined to abdomen. Includes cases with any of the following: a) Involvement of specimen margins grossly or microscopically; b) Tumour in abdominal lymph nodes; c) Diffuse peritoneal contamination by direct tumour growth, tumour implants, or spillage into peritoneum before or during surgery; d) Residual tumour in abdomen e) Tumour removed non-contiguously (piecemeal resection) f) Tumour was surgically biopsied prior to preoperative chemotherapy. SIOP: The presence of necrotic tumour or chemotherapy-induced changes in a lymph node or at the resection margins should be regarded as stage III.

III

IV

COG & SIOP: Hematogenous metastases or lymph node metastasis outside the abdominopelvic region. COG & SIOP: Bilateral renal involvement at diagnosis. The tumours in each kidney should be separately sub-staged in these cases.

V

49

Table 1.08 Histologic criteria for focal anaplasia. - Anaplasia must be circumscribed and its perimeter completely examined (May require mapping of anaplastic foci that extend to the edge of tissue sections) - Anaplasia must be confined to the renal parenchyma - Anaplasia must not be present within vascular spaces - Absence of severe nuclear pleomorphism and hyperchromasia (severe "nuclear unrest") in non-anaplastic tumour.

loose fibromyxoid stroma. An epithelial component of differentiation is present in most nephroblastomas. This pattern may be manifested by primitive rosette-like structures that are barely rec-

ognizable as early tubular forms; other nephroblastomas are composed of easily recognizable tubular or papillary elements that recapitulate various stages of normal nephrogenesis. Heterologous epithelial differentiation may occur, the most common elements being mucinous and squamous epithelium. A variety of stromal patterns may occur and may cause diagnostic difficulty when blastemal and epithelial differentiation, are absent. Smooth muscle, skeletal muscle and fibroblastic differentiation may be present. Skeletal muscle is the most common heterologous stromal cell type and large fields of the tumour often contain this pattern. Other types of heterologous stromal differentiation include adipose tissue, cartilage, bone, ganglion cells, and neuroglial tissue.

thomatous histiocytic foci, haemosiderin deposits and fibrosis. Other chemotherapy-induced changes include maturation of blastema, epithelial, and stromal components, with striated muscle being the most frequent. Remarkable responsiveness to chemotherapy has resulted in complete necrosis in some tumours; such cases are considered to be low risk and may receive minimal treatment after surgery {259}. In contrast, those tumours that do not show response to therapy have a reduced prognosis and increased requirement for therapy.

Post-chemotherapy changes Chemotherapy induces necrosis, xan-

Anaplasia Approximately 5% of nephroblastomas are associated with an adverse outcome and are recognized pathologically because of their "unfavourable" histology due to the presence of nuclear anaplasia {194,318,2952}. Anaplasia is rare during the first 2 years of life, and

A

B

Fig. 1.69 Nephroblastoma. A Primitive epithelial differentiation. B Serpentine blastemal pattern.

A

B

Fig. 1.70 Nephroblastoma. A Skeletal muscle differentiation. B Cytologic appearance of blastemal cells.

50

Tumours of the kidney

increases in prevalence to approximately 13 percent by 5 years of age {934}. Histologic diagnosis of anaplasia requires all of the following:

Presence of multipolar polyploid mitotic figures. In order to qualify for anaplasia each component of the abnormal metaphase, must be as large, or larger, than a normal metaphase. Marked nuclear enlargement and hyperchromasia. The major dimensions of affected nuclei meeting the criteria are at least three times that of non-anaplastic nuclei in other areas of the specimen {2952}. Nuclear enlargement should involve all diameters of the nucleus and should not be confused with simple elongation. The enlarged nucleus must also be hyperchromatic. Anaplasia has been demonstrated to correlate with responsiveness to therapy rather than to aggressiveness. Nonresponsiveness of anaplasia to chemotherapy explains why it is not obliterated by preoperative treatment and therefore may be detected at a somewhat increase in frequency in post-therapy nephrectomy specimens {2759,2952}. Accordingly, anaplasia is most consistently associated with poor prognosis when it is diffusely distributed and when at advanced stages {742}. For these reasons, pathologic and therapeutic distinction, have been made between focal anaplasia and diffuse anaplasia {742}. Focal anaplasia is defined as the presence of one or a few sharply localized regions of anaplasia within a primary tumour, confined to

the kidney, with the majority of the tumour containing no nuclear atypia. The diagnosis of focal anaplasia has restrictive criteria. A tumour with anaplasia not meeting these requirements becomes classified as diffuse anaplasia.

Table 1.09 Conditions associated with nephroblastoma. Syndromes associated with highest risk of nephroblastoma Wilms-Aniridia-Genital anomaly-Retardation (WAGR) syndrome Beckwith-Wiedemann syndrome Hemihypertrophy Denys-Drash syndrome Familial nephroblastoma Conditions also associated with nephroblastoma Frasier syndrome Simpson-Golabi Behmel syndrome Renal or genital malformations Cutaneous nevi, angiomas Trisomy 18 Klippel-Trenaunay syndrome Neurofibromatosis

Immunoprofile The blastemal cells regularly express vimentin, and may also show focal expression of neuron specific enolase, desmin, and cytokeratin {690,786}. Expression of WT-1 is not present in all nephroblastomas, and may be present in various other tumours. In nephroblastomas, it is confined to the nucleus and correlates with tumour histology: areas of stromal differentiation and terminal epithelial differentiation show very low levels or no expression of WT-1, whereas areas of blastemal and early epithelial differentiation show high levels of WT-1 {415,965}.
Somatic genetics Approximately 10% of nephroblastomas develop in association with one of several well-characterized dysmorphic syndromes {493,936}. The WAGR syndrome (Wilms tumour, aniridia, genitourinary malformation, mental retardation) carries a 30% risk of developing nephroblastoma. These patients have a consistent deletion of chromosome 11p13 in their somatic cells involving the WT1 gene {362,860}. WT1 encodes a zinc finger transcription factor that plays a major role in renal and gonadal development {981}. Abnormalities involving WT1 are consistently found in the tumours of WAGR patients as well as in patients with

Bloom syndrome Perlman syndrome Sotos syndrome Cerebral gigantism

Denys-Drash syndrome (a syndrome characterized by mesangial sclerosis, pseudohermaphroditism, and a 90% risk of nephroblastoma). Patients with WAGR have deletions of WT1, whereas patients with Denys-Drash syndrome have constitutional inactivating point mutations in one copy of WT1 and their nephroblastomas show loss of the remaining normal

A

B

Fig. 1.71 Anaplastic nephroblastoma. A Blastemal tumour with multipolar mitotic figures and nuclear enlargement with hyperchromasia. B Anaplasia within the stromal component.

Nephroblastoma

51

Table 1.10 Frequency of paediatric renal malignancies. Neoplasm Estimated relative frequency (%)

Nephroblastoma (nonanaplastic) Nephroblastoma (anaplastic) Mesoblastic nephroma Clear cell sarcoma Rhabdoid tumour Miscellaneous Neuroblastoma Peripheral neuroectodermal tumour Synovial sarcoma Renal carcinoma Angiomyolipoma Lymphoma Other rare neoplasms

80

5

5 4 2 4

WT1 allele {2043}. While WT1 alterations are strongly linked to the development of nephroblastoma in syndromic cases, their role in sporadic nephroblastoma is limited, with only one third of all nephroblastomas showing deletion at this locus and only 10% harbouring WT1 mutations. Beckwith-Wiedemann syndrome (characterized by hemihypertrophy, macroglossia, omphalocele, and visceromegaly) has been localized to chromosome 11p15, and designated WT2 although a specific gene has not been identified {747,1493,2077}. Attempts to determine the precise genetic event at this locus has revealed the presence of a cluster of imprinted genes; whether or not a single gene is responsible for the increased risk for nephroblastoma remains unclear {577}. The preferential loss of the maternal allele at this locus in cases of sporadic nephroblastoma suggests that genomic imprinting is involved in the pathogenesis of some tumours {2000}. Additional genetic loci are associated with familial nephroblastoma in patients with normal WT1 and WT2 {967,

1140,1141,1142,2134}. Approximately 1 percent of patients with nephroblastoma have a positive family history for the same neoplasm. Most pedigrees suggest autosomal dominant transmission with variable penetrance and expressivity. Prognosis and predictive factors Most nephroblastomas are of low stage, have a favourable histology, and are associated with an excellent prognosis. A favourable outcome can be expected even among most neoplasms with small foci of anaplasia. The most significant unfavourable factors are high stage, and the presence of anaplasia. The majority of blastemal tumours are exquisitely sensitive to therapy. However, tumours that demonstrate extensive blastemal cells following therapy are associated with poor response to therapy and reduced survival {197, 259}. In SIOP protocols, these blastemal chemoresistant tumours are classified as "high risk" and are treated like anaplastic tumours.

52

Tumours of the kidney

Nephrogenic rests and nephroblastomatosis

E.J. Perlman L. Boccon-Gibod

Definition Nephrogenic rests are abnormally persistent foci of embryonal cells that are capable of developing into nephroblastomas. Nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests are classified into perilobar (PLNR) and intralobar (ILNR) types. Epidemiology Nephrogenic rests are encountered in 25% to 40% of patients with nephroblastoma, and in 1% of infant autopsies {190,192, 195,210,303}. Histopathology PLNRs and ILNRs have a number of distinguishing structural features.

Table 1.11 Features distinguishing perilobar from intralobar rests. Perilobar rests Position in lobe Margins Composition Peripheral Sharp, demarcated Blastema, tubules Stroma scant or sclerotic Usually multifocal Intralobar rests Random Irregular, intermingling Stroma, blastema, tubules Stroma often predominates Often unifocal

Distribution

Perilobar nephrogenic rests PLNRs are sharply circumscribed and located at the periphery of the renal lobe. A PLNR may be dormant or may

have several other fates: most commonly the rest will regress with peritubular scarring resulting in an obsolescent rest. PLNR may also undergo active proliferative overgrowth, resulting in hyperplastic nephrogenic rests, which can be almost impossible to distinguish from nephroblastoma. Rarely, PLNRs

form a band around the surface of the kidney resulting in massive renal enlargement, (diffuse hyperplastic perilobar nephroblastomatosis). Nephroblastoma developing within a PLNR is recognized by its propensity for spherical expansile growth and a peritumoural fibrous pseudocapsule separating

Fig. 1.72 Diffuse hyperplastic perilobar nephroblastomatosis (upper pole) with two spherical nephroblastomas and an separate perilobar nephrogenic rest in lower pole.

Fig. 1.73 Perilobar nephrogenic rest. Note well demarcated, lens shaped subcapsular collection of blastemal and tubular cells.

Nephroblastoma / Nephrogenic rests and nephroblastomatosis

53

the neoplasm from the adjacent rest and normal kidney.

Intralobar nephrogenic rests In contrast to PLNRs, ILNRs are typically located in the central areas of the lobe, are poorly circumscribed and composed of stromal elements as well as epithelial tubules. Like PLNRs, ILNRs may be dormant, regress, or undergo hyperplasia. Nephroblastoma developing with ILNRs are often separated from the underlying rest by a peritumoural fibrous pseudocapsule.
Prognosis and predictive factors In diffuse hyperplastic nephroblastomatosis, the risk for the development of nephroblastoma is extraordinarily high. Chemotherapy is commonly utilized because it reduces the compressive burden of nephroblastic tissue, which enables normalization of renal function, and reduces the number of proliferating cells that may develop a clonal transformation. There is a high risk of developing multiple nephroblastomas as well as anaplastic nephroblastomas. Therefore, their tumours must be carefully watched and monitored for responsiveness to therapy. In the management of patients with nephroblastomatosis, imaging screening by serial ultrasonography and CT scans enables an early detection of nephroblastoma {191}. Prompt therapy can minimize the amount of native kidney that requires surgical excision (nephron sparing approach), thereby maximizing the preservation of renal function.

Fig. 1.74 Hyperplasia within a large perilobar nephrogenic rest.

A

B
Fig. 1.75 Intralobar nephrogenic rest. A Ill defined proliferation of embryonal cells and intermingling with the native kidney. B Hyperplastic blastemal cells proliferating within the rest intermingling with the native kidney.

54

Tumours of the kidney

Cystic partially differentiated nephroblastoma

J.N. Eble

Definition Cystic partially differentiated nephroblastoma is a multilocular cystic neoplasm of very young children, composed of epithelial and stromal elements, along with nephoblastomatous tissue. ICD-O code 8959/1

Rarely, Wilms tumour may be composed entirely of cysts with delicate septa. Within the septa are small foci of blastema, immature-appearing stromal cells, and primitive or immature epithelium. Such tumours are called "cystic partially differentiated nephroblastoma" {329,1249}. When no nephroblastomatous elements are found, the term "cystic nephroma" has been applied although it is recognized that these lesions are not the same as the morphologically similar ones which occur in adults {646,650}. Cystic partially differentiated nephroblastoma occurs with greater frequency in boys than in girls; almost all patients are less than 24 months old, and sur-

gery is almost always curative {592, 1250,1251}. Joshi and Beckwith reported one recurrence, possibly a complication of incomplete resection {1250}. The tumours often are large, particularly considering the patient's age, ranging up to 180 mm in diameter. Cystic partially differentiated nephroblastoma is well circumscribed from the remaining kidney by a fibrous pseudocapsule and consists entirely of cysts of variable size. The septa are thin and there are no expansile nodules to alter the rounded contour of the cysts. The cysts in cystic partially differentiated nephroblastoma and are lined with flattened, cuboidal, or hobnail epithelium, or lack lining epithelium {1249}. The septa are variably cellular and contain undifferentiated and differentiated mesenchyme, blastema, and nephroblastomatous epithelial elements {1249}. Skeletal muscle and myxoid mesenchyme are present in the septa of most tumours. Cartilage and fat are present occasionally {1250,1251}. Focally, the septal elements may pro-

Fig. 1.76 Cystic partially differentiated nephroblastoma forms a well-circumscribed mass composed entirely of small and large cysts.

trude into the cysts in microscopic papillary folds, or gross polyps in the papillonodular variant of cystic partially differentiated nephroblastoma. The epithelial components consist mainly of mature and immature microscopic cysts resembling cross sections of tubules and stubby papillae resembling immature glomeruli.

A

B

Fig. 1.77 Cystic partially differentiated nephroblastoma. A The septa of cystic partially differentiated nephroblastoma often contain aggregates of blastema. B Pericystic part of the tumour contains immature epithelial elements forming short papillae reminiscent of fetal glomeruli.

Cystic partially differentiated nephroblastoma

55

79 Clear cell sarcoma of the kidney. soft. arborizing fibrovascular Clinical features CCSK comprises approximately 3% of malignant paediatric renal tumours {114}. B Palisading pattern mimicking schwannoma. The mean age at diagnosis is 36 months. 1. CCSK has varied histopathologic pat- A B Fig. Macroscopy CCSKs are typically large (mean diameter 11 cm) and centred in the renal medulla. The frequency of osseous metastases led to the septa {114. A Classic pattern. 1783}. Nuclei are round to oval shaped. and lack prominent nucleoli. have fine chromatin.78 Clear cell sarcoma of the kidney.Clear cell sarcoma P. tan. regularly branching "chicken-wire" capillaries.1311.196.1629. Argani Definition Clear cell sarcoma of the kidney (CCSK) is a rare paediatric renal sarcoma with a propensity to metastasize to bone. and are loosely separated by extracellular myxoid material that mimics clear cytoplasm. they characteristically have subtly infiltrative borders. and almost always focally cystic. The male to female ratio is 2:1. . B Acinar pattern mimicking nephroblastoma.1630. 1.1628. Histopathology The classic pattern of CCSK features nests or cords of cells separated by regularly spaced. and mucoid. and always unicentric. or thickened sheaths of fibroblastic cells surrounding a central capillary. A Trabecular pattern. ICD-O code 9044/3 proposed name "bone metastasizing renal tumour of childhood" {1630}. CCSK is not associated with Wilms tumourrelated syndromes or nephrogenic rests. entrapping isolated native nephrons. While CCSKs are grossly circumscribed. The cord cells may be epithelioid or spindled. A 56 Tumours of the kidney B Fig. CCSK are unencapsulated but circumscribed. The septa may be thin.

781}.81 Clear cell sarcoma of the kidney. bone metastases are the most common mode of recurrence {1628. MIC2 (CD99). Prominent palisaded.A B Fig. The cytoplasm has scattered intermediate filaments {980}. whereas epithelioid (trabecular or pseudoacinar) patterns may mimic Wilms tumour. A Sclerosing pattern mimicking osteoid. CCSK is also distinguished from Wilms tumour by its proclivity to metastasize to unusual sites such as (in addition to bone) brain. spindled and storiform patterns mimic other sarcomas. The cord cells of CCSK have a high nucle- Fig. with thin cytoplasmic extensions surrounding abundant extracellular matrix. 1. S100 protein. and the orbit.935}. CCSK is uniformly negative with CD34. metastases may occur as late as 10 years after initial diagnosis.1629}. desmin. Approximately 3% of CCSKs are anaplastic. Clear cell sarcoma 57 . A cellular pattern mimics other paediatric small round blue cell tumours. and epithelial membrane antigen {114}. terns. while hyaline collagen simulating osteoid characterizes the sclerosing pattern. Prognosis and predictive factors The survival of patients with CCSK has increased from only 20% up to 70% due in large part to the addition of adriamycin (doxorubicin) to chemotherapeutic protocols {114. soft tissue. B Myxoid pools and cellular septa. While involvement of perirenal lymph nodes is common at diagnosis (29% of cases). Cellular pattern mimicking Wilms tumour. Immunoprofile / Ultrastructure While vimentin and BCL2 are typically reactive. Nonetheless. us/cytoplasm ratio.80 Clear cell sarcoma of the kidney. Pools of acellular hyaluronic acid lead to the myxoid pattern {781}. 1. cytokeratin. Post-therapy recurrences may adopt deceptively-bland appearances simulating fibromatosis or myxoma {114.

Rhabdoid tumour P. 1. Histopathology These tumours are unencapsulated. A 58 Tumours of the kidney B Fig. and hyaline pink cytoplasmic inclusions. 1.83 Rhabdoid tumour showing extensive tumour necrosis and haemorrhage. but on closer inspec- tion small foci of cells with diagnostic cytologic features can be identified. and hyaline intracytoplasmic inclusions. prominent nucleoli. A subset of tumours may be composed predominantly of primitive undifferentiated small round cells. Clinical features The most common presentation is that of haematuria. Ultrastructure The cytoplasmic inclusions correspond to whorls of intermediate filaments having a diameter of 8 to 10 nm. Immunoprofile Nonspecific trapping of antibodies by the whorled cytoplasmic inclusions can give a wide range of false positive results. Tumour cells characteristically display the cytologic triad of vesicular chromatin. The diagnosis is highly suspect over the age of 3. prominent cherry-red nucleoli. The nucleus is vesiculated. The most consistent and characteristic finding is that of strong vimentin labeling and focal but intense labeling for EMA. and feature sheets of tumour cells that aggressively overrun native nephrons. and approximately 80% of patients are diagnosed in the first 2 years of life. Most previously reported RTKs over the age of 5 have subsequently proven to be renal medullary carcinomas {2795}. Epidemiology Rhabdoid tumour comprises approximately 2% of all paediatric renal tumours. and virtually nonexistent over the age of 5.84 A. B Rhabdoid tumour of the kidney. haemorrhagic and necrotic. ICD-O code 8963/3 Fig. The mean age at diagnosis is approximately 1 year. Approximately 15% of patients will develop a tumour of the posterior fossa of the brain that resembles PNET morphologically. Macroscopy Tumours are typically large. Argani Definition Rhabdoid tumour of the kidney (RTK) is a highly invasive and highly lethal neoplasm of young children composed of cells with vesicular chromatin. with ill defined borders that reflect its highly invasive nature. CT showing large focally cystic tumour (left). A significant number of patients present with disseminated disease. The cytoplasm contains eosinophilic inclusions. 1.82 Rhabdoid tumour. . Vascular invasion is usually extensive. Fig.

1. A familial "rhabdoid predisposition syndrome" encompassing renal and extrarenal rhabdoid tumours has been described in which affected family members harbour constitutional inactivation of hSNF5/INI1 {2368. Inactivation of this gene is also seen in morphologically similar rhabdoid tumours which occur in the soft tissue. Inactivation occurs via mutation. confirming the clinicopathologic impression that these are independent neoplasm {790. as over 80% of patients will die of tumour within 2 years of diagnosis. All of these tumours typically affect young children.2729}. Note characteristic vesicular chromatin. B Nuclei are angulated with prominent nucleoli. and are usually lethal.2588}. is the molecular hallmark of RTK {242. A Fig. brain.2311}. Somatic genetics Biallelic inactivation of the hSNF5/INI1 tumour suppressor gene. Inactivation of the second allele has been shown to occur by different mechanisms in these patients’ two cancers. Rhabdoid tumour 59 . deletion or whole chromosome loss. The rare patients who present with tumour confined to the kidney may have a slightly better prognosis. A Strong cytoplasmic vimentin immunoexpression. and its inactivation is thought to promote neoplasia by altering gene expression secondary to its effect upon chromatin structure. 1. 1. and occasionally other visceral sites. which resides on the long arm of chromosome 22. Prognosis and predictive factors Outcome is typically dismal. A Note sheet-like diffuse growth of monomorphic tumour cells overrunning a native glomerulus.A B Fig. B Fig.87 Rhabdoid tumour of the kidney. Children with concurrent RTK and PNETlike tumours of the posterior fossa of the CNS frequently harbour germline mutations in the hSNF5/INI1 gene {241}. B Transmission electron micrograph showing intracytoplasmic intermediate filiments. The hSNF5/INI1 gene encodes a protein involved in chromatin remodeling that is thought to regulate the accessibility of transcription factors to DNA.86 Rhabdoid tumour of the kidney.85 Rhabdoid tumour of the kidney. accounting for the frequent cytogenetic finding of monosomy 22 in these neoplasms. prominent nucleolus and hyalin intracytoplasmic inclusion.

Tumours are composed of interlacing fascicles of fibroblastic cells with thin tapered nuclei.1845}. NTRK3 is a tyrosine kinase receptor that responds to extracellular signals.2255}. cellular type. 1. Interestingly.q25).B. t(12. Cellular CMN but not classic CMN demonstrates a specific chromosome translocation. high cellularity and ill-defined fascicles. whorled texture. cystic and haemorrhagic. Somatic genetics While classic CMNs are typically diploid. Note haemangiopericytomatous vascular pattern. The tumour dissects and entraps islands of renal parenchyma. cellular CMNs frequently feature aneuploidy of chromosomes 11. CMN is the most common congenital renal neoplasm. the same chromosome translocation and gene fusion present in cellular CMN was first identified in infantile fibrosarcoma. which results in a fusion of the ETV6 and NTRK3 genes {1336.Congenital mesoblastic nephroma P. and frequently features necrosis. Argani P. and are composed of poorly formed fascicles. appears appropriate. ICD-O code 8960/1 Clinical features CMN comprises two percent of paediatric renal tumours {193.H.2063. low mitotic activity.15)(p13. and ninety percent of cases occur in the first year of life. the analogy between cellular CMN and infantile fibrosarcoma. Histopathology Classic CMN (24% of cases) is morphologically identical to infantile fibromatosis of the renal sinus {265}. {1377. which give way to sheet-like growth patterns. The tumour shows a high mitotic rate. cellular type. Cellular CMN (66% of cases) is morphologically identical to infantile fibrosarcoma. tumours have features of myofibroblasts or fibroblasts. Mixed CMN (10% of cases) has features of both classic and cellular CMN within the same tumour.88 A.2338}. 1. B Congenital mesoblastic nephroma. Sorensen Definition Congenital mesoblastic nephroma (CMN) is a low-grade fibroblastic sarcoma of the infantile kidney and renal sinus. The typical presentation is that of an abdominal mass. and is not present in infantile fibromatosis {1337}. The oncogenic mechanism of the ETV6NTRK3 gene fusion remains to be determined. pink cytoplasm. ETV6 is an ETS transcription factor previously implicated in translocations in paediatric B-cell acute lymphoblastic leukaemia. and between classic CMN and infantile fibro- matosis. ETV6-NTRK3 fusion transcripts encode a chimeric protein in which the sterile-alpha-motif (SAM) protein dimerization domain of the ETV6 A B Fig. Ultrastructurally. Immunoprofile These tumours are immunoreactive for vimentin and often actin with desmin reactivity being rare and CD34 being absent. and 17 Fig. and an abundant collagen deposition. These tumours have a pushing border. 8. while cellular CMN are more typically soft. Macroscopy Classic CMN has a firm.89 Congenital mesoblastic nephroma. 60 Tumours of the kidney . Hence.

Note fascicles of fibroblastic cells resembling fibromatosis dissecting the native kidney.2764}. Note that the left half is identical to classic type and the right half is identical to the cellular type. which is mediated by ligand-independent homodimerization through the SAM domain and activation of the PTK domain. CMN is associated with an excellent prognosis.1337}. which show embryonal hyperplasia. Only rare cases of hematogenous metastases and tumour related deaths have been reported {1051. which was recently shown to be essential for EN transformation {1788}. and both are required for EN transformation {1516. Congenital mesoblastic nephroma 61 . 1. Prognosis and predictive factors When completely excised.transcription factor is fused to the protein tyrosine kinase (PTK) of NTRK3.2621. A Mixed type. Virtually all congenital fibrosarcoma and cellular CMN cases expressing ETV6NTRK3 also have trisomy 11 {1336. A B C Fig. B Classic type. One intriguing possibility is that trisomy 11 provides cells with an additional copy of the 11p15. which is related to the incompleteness of resection and not to whether the tumour was of cellular or classic type.2758}. IGF2 binds to the insulin-like growth factor 1 receptor.5 gene (IGF2) encoding the insulin-like growth factor (IGF)-2 anti-apoptotic factor {178}. namely the Ras-MAP kinase (MAPK) mitogenic pathway and the phosphatidyl inositol-3kinase (PI3K)-AKT pathway mediating cell survival. ETV6NTRK3 (EN) has potent transforming activity in murine fibroblasts.90 Congenital mesoblastic nephroma. Five percent of patients develop recurrence. Note fascicles of fibroblastic cells adjacent to native renal tubules. This in turn constitutively activates two major effector pathways of wild-type NTRK3. C Classic type.

Vieillefond G. ORTI is grossly well circumscribed and measures 1-6 cm in diameter. Osteoid meshwork interspersed with cuboidal cells. the tumour cells are positive for CD34. Sheets of uniform spindle cells with ovoid nuclei may entrap renal tubules. ICD-O code 8967/0 ORTI is extremely rare. there is a characteristic coarse trabecular osteoid meshwork Fig.91 Ossifying renal tumour of infancy. Most of them arise in the renal sinus and the perirenal tissue. 1.1184.2462. Keen Definition Ossifying renal tumour of infancy (ORTI) is an intracalyceal mass composed of osteoid trabeculae. only 12 cases have been reported in the English literature {414. Behaviour of haemangiopericytoma is difficult to predict.1715. osteoblast-like cells and a spindle cell component. firm and histologically composed of a proliferation of fusiform pericytes separated by numerous capillaries presenting a staghorn configuration. These tumours are large. 62 Tumours of the kidney . negative for CD31. All cases presented with gross haematuria except one which manifested as a palpable abdominal mass. but not cytokeratin. These two entities share almost the same histological pattern and the same imprecise potential of malignancy. Calcification of the tumour frequently suggests renal calculus. No cases have been reported in association with Wilms tumour or with WT1/WT2 gene syndromes on chromosome 11p. The exact nature of ORTI spindle cells is still uncertain. Microscopically. Late recurrence or metastases can never be excluded.1992}. like hypoglycemia or hypertension. Males predominate (9/12). The outcome has been uniformly benign and conservative surgical management is recommended. Haemangiopericytoma A. and attached to the medullary pyramid. de Pinieux ICD-O code 9150/1 Less than 30 primary renal haemangiopericytomas are reported in the literature `788. actin and CD99.2715}. Age at presentation was 6 days to 17 months. may occur. Paraneoplastic syndromes. Immunohistochemically.E. especially when the tumour size is over 5 centimeters and mitotic rate over 4 per 10 HPF. arising from.Ossifying renal tumour of infancy C. There are no specific radiological features. with interspersed large cuboidal osteoblast-like cells that express EMA as well as vimentin. Some haemangiopericytomas of the literature could be reevaluated as solitary fibrous tumours {1595}.

Small size (< 5 cm). ICD-O code 8890/3 Epidemiology Although leiomyosarcoma is a rare primary renal neoplasm. Fig. The prognosis of primary renal osteosarcoma is very poor despite aggressive therapeutic approach combinating radical surgery. radiotherapy and polychemotherapy.}.1919. 306. primary renal osteosarcoma shows a pleomorphic pattern and consists of spindle and multinucleated giant tumour cells producing neoplastic osteoid and bone. 1. Clinical features Patients usually present with flank pain. the more common sarcomatoid carcinomas. focally necrotic tumours. but high grade lesions are pleomorphic and undifferentiated. they may replace large portions of the parenchyma.2742}. therefore. It metastasizes to lung. If parenchymal in origin. Bonsib Definition A leiomyosarcoma is a malignant neoplasm demonstrating smooth muscle differentiation.M. Histologically.950. Low grade lesions resemble smooth muscle cells. Compared to osteosarcoma of bone. Renal pelvic tumours fill the collecting system. plexiform. Necrosis. Irradiation and chemotherapy are ineffective. and renal-limited disease are associated with the most favourable outcome. The male/female ratio is roughly equal. it is the most common renal sarcoma accounting for 5060% of cases {950. or haphazard growth pattern. Vieillefond G. or the main renal vein {273. Macroscopy Leiomysarcoma may arise from the renal capsule. pelvic muscularis. there are no specific symptoms. requiring immunohistochemical stains to separate from other sarcomas. and men and women are equally affected. Leiomyosarcomas are usually large solid grey-white. Clinically. soft to firm. it occurs in older patients. haematuria and a mass. and more than a rare mitotic figure indicate malignancy. Most occur in adults. Pathogenesis of these tumours remains unclear and their relationship with carcinosarcoma may be suggested.1816. and from atypical forms of epithelioid angiomyolipoma {274}. and may invade the renal parenchyma or extend into the sinus or hilar perirenal fat. Leiomyosarcoma is aggressive with a 5-year survival rate of 29-36%.274. complete surgical extirpation is the only therapy. renal parenchyma. and extend through the renal capsule and into the renal sinus. Histopathology Leiomyosarcomas are spindle cell lesions with a fascicular. of over 40 years of age. most patients die of disease within 1-year of diagnosis. Pelvic leiomyosarcoma may be regarded as a transitional cell carcinoma until microscopic examination is performed. liver.Leiomyosarcoma S. low histological grade. Early local recurrence and/or metastatic spread (especially pulmonary) are frequently observed.2742}. Osteosarcoma A. Nearly all the tumours exhibit a high stage (T3 or T4) at time of diagnosis. They may envelope the kidney if capsular in origin.92 Leiomyosarcoma of the renal vein. Tumours arising in the capsule or parenchyma cannot be distinguished from other renal cortical neoplasms by imaging studies.2800. Ossifying renal tumour of infancy / Haemangiopericytoma / Leiomyosarcoma / Osteosarcoma 63 . and bone. nuclear pleomorphism. de Pinieux ICD-O code 9180/3 Primary osteosarcoma of the kidney is an exceedingly rare neoplasm with less than 20 cases reported in the literature {1716.

Vieillefond G. Some angiosarcomas produce cytokeratin. The two main differential diagnoses are leiomyosarcoma.Renal angiosarcoma H. de Pinieux ICD-O code 8830/3 Less than 50 renal MFH are documented in the literature {1269. 1. Clinical symptoms are flank pain. ICD-O code 9120/3 the renal capsule. Histopathology Microscopically. Bizarre nuclei and multinucleated cells may be seen. haemorrhagic spongy masses. the tumours consist of illdefined. CD31 and CD34. Most of them have pararenal and retroperitonal extension and are considered to arise from the renal capsule.2581}. Arnholdt Definition Primary renal angiosarcomas are exceedingly rare aggressive tumours of endothelial cells. Poorly differentiated areas are composed of large sheets of spindled or epithelioid cells that are diffult to distinguish from other sarcomas or carcinomas. Mitotic figures are frequently identified. An androgen factor has been discussed because of a strong male predominance (ratio 19:4) and experimental data {420}. Malignant fibrous histiocytoma A.1096. which are much more frequent than MFH. Prognosis and predictive factors Prognosis of renal angiosarcoma is poor with rapid development of haematogenous metastasis. The etiology is unknown. CD31 seems to be the more sensitive and more specific antigen for endothelial differentiation. Epithelioid/pleomorphic angiomyolipoma and secondary intrarenal extension of a perirenal dedifferentiated liposarcoma may also be considered. rounded or irregular in outline with hyperchromatic and elongated or irregular nuclei. Myxoid and inflammatory MFH variants may occur in the kidney. Localization and clinical features Primary renal angiosarcomas occur near Immunoprofile Immunohistochemical confirmation of the diagnosis of angiosarcoma can be accomplished using antibodies directed against factor VIII. The tumour cells are spindle-shaped. This differential diagnosis relies on immunohistochemistry and extensive sampling of the tumour to exclude a tiny carcinomatous component. they show the same changes that characterize other angiosarcomas. Epidemiology About 23 cases of this tumour have been documented {396. Diagnosis of MFH relies on morphologic criteria {1845}: pleomorphic cells (spindle.1502}. The mean survival of the 19 documented cases is 7.7 months. 64 Tumours of the kidney . They can extend into the renal and caval veins.1447.93 Malignant fibrous histiocytoma. Some areas may reveal well-differentiated neoplastic capillary-size vessels comparable to haemangiomas or less well-differentiated vessels with rudimentary lumen formation and pleomorphic tumour cells. the most frequent renal (or capsular) sarcoma and sarcomatoid carcinoma. haematuria. round histiocyte-like and multinucleated giant tumour cells) arranged haphazardly in sheets or in short fascicles in a storiform pattern (storiform-pleomorphic type). palpable tumour and weight loss. Fig. Macroscopy Grossly. The mean age is 58 years (range 30 to 77 years). Synonym Haemangiosarcoma. They are large fleshy tumours with haemorrhage and necrosis.

2503. 1. or a combination of these signs and symptoms. which is present in most AMLs. The etiology and pathogenesis of the neoplasm are unknown. It can occur sporadically or in patients with TS. 1825.2707. Etiology AML is believed to belong to a family of lesions characterized by proliferation of perivascular epithelioid cells (PEC) {268.Angiomyolipoma G. Lesions may be multifocal {2570}. rence of AML with renal cell carcinoma (RCC) and oncocytoma in the same kidney has also been reported {1224}.B.785. Multifocal AML in the kidney indicates a presumptive diagnosis of TS. and abnormal thick-walled blood vessels. 1. a progressive disease which usually affects the lungs of young women and which is also related to TS. Martignoni M.95 A Angiomyolipoma.2920}.917. Simultaneous occur- Fig. ICD-O code 8860/0 Epidemiology Age and sex distribution In surgical series which are usually overrepresented by non-tuberous sclerosis (TS) cases there is a 4:1 female predominance {1299.1103. Amin Definition Angiomyolipoma (AML) is a benign mesenchymal tumour composed of a variable proportion of adipose tissue. but there is no apparent sex predilection in TS patients with AML detected by imaging techniques {487}. palpable mass.2503. Large tumour with hemorrhagic component.2909}. High fat content. is responsible for a distinctive pattern on a CT scan. but its frequency is increasing because it is detected in ultrasonographic examinations performed to evaluate other conditions {816}. Renal angiosarcoma / Malignant fibrous histiocytoma / Angiomyolipoma 65 .2920}. 269. Incidence AMLs account for approximately 1% of surgically removed renal tumours.1825.2511.2570. Recent molecular studies have demonstrated its clonality {933. B A large tumour with high lipid content. an inherited autosomal dominant syndrome {910}. Tumours composed predominantly of smooth muscle cells or with an admixture of all three compo- A B C Fig. In TS. Histopathological and genetic studies have demonstrated that AML and LAM share numerous features {268.2503. and immunohistochemical and ultrastructural studies support the idea of histogenesis from a single cell type {269.94 Angiomyolipoma of the kidney. spindle and epithelioid smooth muscle cells. Another interesting aspect of AML is the association with lymphangioleiomyomatosis (LAM). Localization AMLs may arise in the cortex or medulla of the kidney. CT scan of angiomyolipoma characterized by high fat content. depending on the presence or absence of TS.2628}. Match with CT.2628}.1171. Imaging Computerized tomography (CT) and ultrasonography permit the preoperative diagnosis of AML in almost all cases. bulging into the perirenal fat is seen. The mean age at diagnosis in surgical series is between 45 and 55 for patients without TS and between 25 and 35 for those with TS {1299. Extrarenal growth in the retroperitoneal space with or without renal attachment can occur. It has been considered an uncommon neoplasm. C Multiple angiomyolipomas of the kidney.2008}.1825. Most surgical series report four times as many sporadic AMLs as AMLs associated with TS {1299. Clinical features Signs and symptoms Clinical features differ.2628}. Retroperitoneal haemorrage may occur {2503}. haematuria. It is possible that puberty influences the development of AML {487}. Patients without TS present with flank pain. the onset of AML after puberty and the frequent progesterone receptor immunoreactivity in AML {1077} suggest a hormonal influence. The different frequency of AML in females and males in the surgical series. AMLs are usually asymptomatic and discovered by radiographic screening techniques.

Tumours composed of all three components may mimic a clear cell RCC whereas a smooth muscle predominant AML may mimic a leiomyoma. striking degrees of nuclear atypia (occasionally with mitotic activity and multinucleation) may be seen in these cells. whereas epithelial markers are always negative {125. Most AMLs are solitary.762. and desmin may also be positive. thus mimicking a liposarcoma when there is extensive adipocytic differentiation. CD63. The smooth muscle cells appear to emanate from blood vessel walls in a radial fashion.757. branching vessels with a pattern similar to lymphangioleiomyoma is another variation of the smooth muscle component. Mart1/Melan A and microophthalmia transcription factor) and smooth muscle markers (smooth muscle actin.1636}. but not encapsulated. arising in the renal interstitium. muscle-specific actin and calponin). supplemented if necessary by immunohistochemistry {275}. estrogen and progesterone receptors. angiomyolipoma may closely resemble renal oncocytoma.97 Angiomyolipoma. The lipomatous component consists typically of mature adipose tissue but may contain vacuolated adipocytes suggesting lipoblasts. Prominent cystic change may very rarely be present in AML. Immunoprofile AMLs are characterized by a coexpression of melanocytic markers (HMB45. Some AMLs that are often located subcapsularly and composed almost entirely of smooth muscle cells ("capsulomas") resemble leiomyomas.1254. The blood vessels are thick-walled and lack the normal elastic content of arteries. HMB50. AMLs with a prominent vascular component may mimic a vascular malformation. Vascular invasion and multifocality have occasionally been misinterpreted as evidence of malignancy and metastasis.96 Angiomyolipoma. Tumour spread and staging Infrequently. CD68. raising the possibility of malignancy. 66 Tumours of the kidney . they bulge into rather than infiltrate the perirenal fat.2570}. neuron-specific enolase. Regional lymph node involvement can occur. depending on the relative proportions of the various tissue components. 1. thick-walled poorly organized blood vessels and smooth muscle (classic triphasic histology). In some of these cases the diagnosis is possible by fine-needle aspiration. Scattered HMB45 positive cells within cytologic specimen. the renal vein or the vena cava. a large dominant tumour associated with smaller lesions is typical. B Cytologic specimen from renal angiomyolipoma. but multiple tumours may be present. Histopathology Most AMLs are composed of a variable mixture of mature fat. Although AMLs may grow to great size. 1258. two patients had pulmonary metastases and one had hepatic metastases {466. S-100 protein. although renal tubules may be entrapped at the periphery of some tumours. A Deposit of angiomyolipoma in a para-aortic lymph node in the drainage basin of a kidney bearing an angiomyolipoma. Cells associated with thin-walled. The smooth muscle cells are most frequently spindle cells but may appear as rounded epithelioid cells. Coexpression of A B Fig.1419. The border between AML and the kidney is typically sharp. Rarely. nents or with prominent cystic change may be difficult to distinguish from an epithelial neoplasm preoperatively {2388}.2922}. A Microscopic angiomyolipoma composed of smooth muscle with a minority of fat cells. and expansile growth thereafter may be fascicular. it is considered to represent a multifocal growth pattern rather than metastasis {18. tyrosinase.2037. B Rarely. in such situations. Macroscopy AMLs usually are well demarcated from the adjacent kidney. 1.A B Fig. The colour varies from yellow to pinktan. Only three cases of sarcoma developing in sporadic AML have been reported. AML extends into the intrarenal venous system.

The TSC2 gene is located on chromosome 16p13. SMA expression.1632. Fig. 1078}. Intraglomerular lesions with features Somatic genetics Two genes are known to cause TS. a 180 kDa GTPase-activating protein for RAP1 and RAB5 {2604}.98 Angiomyolipoma of the kidney. 2088}. LOH of TSC2 gene locus in both sporadic and tuberous sclerosis-associated tumours. Haemorrhage into the retroperitoneum. Prognosis and predictive factors The classic AMLs are benign. AMLs show spindle cells with features of smooth muscle cells. 1. The smallest nodules are often composed predominantly of epithelioid smooth muscle cells. TSC1 gene is involved occasionally in LOH. may be life threatening.2796. usually in tumours greater than 4. The TSC1 gene is located on chromosome 9q34. 1. suggesting that these lesions may be the source of AMLs.0 cm or in pregnant patients. Precursor lesions Small nodules with some features of AML are often present in the kidney bearing AMLs.2913}.melanocytic and smooth muscle markers in myoid-appearing and lipid-distended cells supports the unitary nature of AML being a neoplasm with ability for phenotypic and immunotypic modulation. Some spindle cells contain lipid droplets indicating transition forms between smooth muscle cells and adipocytes {1103}. Angiomyolipoma 67 . consists of 23 exons and encodes hamartin. Fig. overlapping those of AML have been reported in patients with and without TS {1315. and intracytoplasmic membrane-bound dense bodies. Renal cysts and multiple AMLs in TS patients can lead to renal failure {2321}. forming a cytoplasmic complex {1878. A very small minority are associated with complications and morbidity and mortality {1936}. Tuberin and hamartin interact with each other. consists of 41 exons and encodes tuberin.1865}. and the proportion of spindle cells and adipocytes increase as the lesions become larger {459}. a 130 kDa protein {2704}.99 Intraglomerular lesion associated with angiomyolipoma of the kidney. Focal positive immunoreactivity to actin in a glomerulus containing a group of smooth muscle epithelioid cells. Ultrastructure Ultrastructurally. AML frequently shows loss of heterozygosity (LOH) of variable portions of TSC2 gene locus in both sporadic and TS-associated tumours {370. crystals and granules (rhomboid and spherical) have been linked to renin and premelanosomes without conclusive or consistent evidence {1825. Ultrastructural evidence of melanogenesis is reported.

1. Amin Definition Epithelioid angiomyolipoma (AML) is a potentially malignant mesenchymal neoplasm characterized by proliferation of predominantly epithelioid cells and is closely related to the triphasic (classic) AML.1346}.593. A B Fig. Necrosis may be present. Extrarenal extension or involvement of the renal vein/vena cava may occur. which is a significantly higher association than classic AML has with TS {50.100 Epithelioid angiomyolipoma. Tumour cells are round to polygonal with enlarged vesicular nuclei often with prominent nucleoli. brown or haemorrhagic appearance. 1. Macroscopy Tumours are usually large. A Marked nuclear atypia and mitotic figures may be present. The mean age of diagnosis is 38 years {649. some patients are discovered during TS follow-up.466.463. A Epithelioid angiomyolipoma is typically composed of a mixture of polygonal and spindle cells of variable size. B Immunohistochemical reaction with HMB-45 shows numerous positive cells. often with perivascular cuffing of epithelioid cells.2036. presenting with pain. Inflammatory cells often are mingled with the neoplastic cells.B. Histopathology There is a proliferation of epithelioid cells with abundant granular cytoplasm arranged in sheets.1634}. Epidemiology More than half of patients with epithelioid AML have a history of tuberous sclerosis (TS). B Focally ganglion like and multinucleated cells are present.1606. white. 68 Tumours of the kidney . Both sexes are equally affected similar to classic AML occurring in TS patients. A B Fig.463.50.224}. with infiltrative growth and a grey-tan. Imaging studies closely mimic renal cell carcinoma because of the paucity of adipose tissue {1289.Epithelioid angiomyolipoma M. Clinical features Patients are frequently symptomatic.101 Epithelioid angiomyolipoma. Many of the reported cases were initially misdiagnosed as a high grade carcinoma.

2863}. Mart1/Melan-A and microphthalmia transcription factor) with variable expression of smooth muscle markers (smooth muscle actin. A few cases have focal classic AML areas {649. HMB-50. Variations in histology include variable admixture of clear cells. necrosis and infiltration of perinephric fat. mitotic activity. none correlate with outcome. however. 2922.466}. Prognostic and predictive factors Approximately one-third of epithelioid AML have been reported to have metastasis to lymph nodes.1419.2863}. Tumours may display nuclear anaplasia.1636. Haemorrhage often is prominent.2036. epithelioid and sarcomatoid areas indicating clonality and relationship {2497}. markers (HMB-45.2511}. mitotic activity. although occasionally they may predominate {2184. nuclear anaplasia and extrarenal spread should raise significant concern for malignant outcome {463.Multinucleated and enlarged ganglion-like cells may be present. lungs or spine {1565.757. tumours with necrosis.560}. Immunoprofile Epithelioid AML expresses melanocytic Epithelioid angiomyolipoma 69 . muscle-specific actin) {125. TP53 mutation is detected in epithelioid but not triphasic AML. Genetics Allelic loss of chromosomal arm 16p (TS2 containing region) is noted in classic. A population of short spindle cells is present in many tumours. suggesting a role in malignant transformation {1289}.466.757. vascular invasion. Among adverse pathologic parameters. liver.

Histopathology Histologically. 1. 70 Tumours of the kidney .1762. They may on occasion be large (largest case reported 37 kg). or from cortical vascular smooth muscle {273. resulting in surgery for a presumed carcinoma {273. 2585}. demonstrating a positive reaction on actin and desmin stains {273. usually arranged in intersecting fascicles with little nuclear pleo- Epidemiology and etiology A leiomyoma may arise from the renal capsule (most common).2502. Most are encountered in adults as incidental small mm-sized capsular tumours at autopsy. suggesting a relationship to angiomyolipoma and other tumours of the perivascular epithelioid cell family of tumours {273}. Fig.508. they are composed of spindled cells. ICD-O code 8890/0 examples have a trabeculated cut surface.624. Some focally express HMB-45. 1. Large morphism and no mitotic activity. but necrosis should not be present.2502}. 2585}. A 5 cm leiomyoma with several mm-sized capsular leiomyomas. They have a smooth muscle immunophenotype.624.102 Leiomyoma. muscularis of the renal pelvis. leiomyomas are firm well-demarcated solid lesions.Leiomyoma S. Bonsib Definition Leiomyoma is a benign smooth muscle neoplasm.103 A leiomyoma composed of uniform spindle cells arranged in fascicles without mitotic activity.M. Fig. Macroscopy Macroscopically. Calcification and cystic change have been described.

Smooth muscle may be present as in lymphangiomas elsewhere.578}. i. Epidemiology These tumours most commonly affect young to middle aged adults. rarely these tumours may be found in the renal cortex or the renal capsule {2779}. A bilateral presentation in children is referred to as lymphangiomatosis {1462}.M. Colicky pain may also be noted. Clinical features Symptomatic patients present with recur- Lymphangioma S. Renal pyramids and renal pelvis are the most common sites of involvement.e. haemangiomas may be part of a syndrome such as SturgeWeber syndrome. ICD-O code 9170/0 Epidemiology and etiology These lesions are more common in adults.2916}. Children account for 1/3 of cases. irregular blood-filled vascular spaces lined by a single layer of endothelial cells. Macroscopy Lymphangiomas are encapsulated. and are composed of fibrous septae lined by flattened endothelium that is factor VIII and Ulex europaeus agglutinin positive but cytokeratin negative. The fibrous septa may contain small bland entrapped native tubules and lymphoid cells.Haemangioma P. and defects in the von Hippel Lindau gene {358. trisomy 7q. On cut sec- tion they are unencapsulated. or most often. have a spongy red appearance. develop within the cortex. Some cases appear neoplastic with karyotype abnormalities such as monosomy X. Klippel-Trenaunay syndrome and systemic angiomatosis. ICD-O code 9120/0 rent episodes of hematuria. A number of these tumours are asymptomatic and are discovered incidentally at autopsy {1205}. however. In addition to sporadic tumours. They may show an infiltrative growth pattern. Histopathology Both capillary and cavernous haemangiomas have been reported. Tamboli Definition Haemangioma is a benign vascular tumour that occasionally arises in the kidney. arising in a renal vein. A case of intravascular capillary haemangioma. Leiomyoma / Haemangioma / Lymphangioma 71 . There is no sex predilection. Macroscopy Haemangiomas are generally unilateral and single. The largest haemangioma reported to date was 18 cm in greatest diameter {2875}. the latter being more common.2921}. caused by the passage of blood clots. or may be apparent as a small red streak. contain clear fluid. present as a peripelvic or renal sinus mass. Some cases may develop secondary to inflammatory lower urinary tract diseases. but may rarely be multifocal or bilateral {2573. the youngest reported patient was a newborn {2916}. They exhibit the typical histologic features of haemangiomas. and presenting as a renal mass has also been reported {1145}. Bonsib Definition Lymphangioma is a rare benign renal tumour that may arise from the renal capsule. diffusely cystic lesions ranging from small well-delineated tumours to large (19 cm) lesions that replace the entire renal parenchyma {89. but lack the mitosis and nuclear pleomorphism seen in angiosarcomas.1867. They are usually treated by nephrectomy because preoperative investigations cannot distinguish them from a malignant neoplasm. Histopathology The cysts communicate. or represent a developmental abnormality in lymphatic formation.

72 Tumours of the kidney . the tumour may contain channels lined by epithelium.106 Juxtaglomerular cell tumour. Clinical features The diagnosis of JGCT is usually suspected in patients with severe poorly controlled hypertension and marked Epidemiology Since the first description in 1967 {2213} over 60 JGCTs have been reported {1638}. 1. 1. B Rarely.105 Juxtaglomerular cell tumour. averaging 27 years. Têtu Definition Juxtaglomerular cell tumour is a benign renin-secreting tumour. cortical and arises equally in both kidneys and in either pole. JGCT usually occurs in younger individuals. A Occasionally. ICD-O code 8361/0 despite an interval of up to 17 years between the onset of hypertension and nephrectomy {1790} and a follow-up of up to 17 years after surgery {978}. A B Fig. and is twice as common in women.104 Juxtaglomerular cell tumour. 1. A B Fig. There is no reported recurrence or metastasis Fig. B Higher magnification demonstrates pale halos about the nuclei.Juxtaglomerular cell tumour B. extensively papillary architecture may be seen. A Solid growth pattern of polygonal cells. Localization JGCT is unilateral.

A variable number of round electrondense mature renin-like granules are also found. vimentin and CD34 {1638}. PAS and toluidine blue. 1. Mast cells and thick-walled hyalinized blood vessels are common and.A Fig. Electron micrograph showing irregular rounded renin-containing granules (A) and rhomboid crystalline renin granules (B). 1. 1. elevated secondary hyperaldosteronism and a renal mass. although one patient presented with normal blood pressure {1044}. hypokalemia.107 Juxtaglomerular cell tumour. Rarely. a well developed Golgi apparatus and numerous peripherally located sharply angu- lated rhomboid renin protogranules. The tumour is usually smaller than 3 cm in diameter but cases ranging from 2 mm {1097} to 9 cm {1413} have been reported. Typically. in about one-half of reported cases. JGCT may be largely papillary {2602}.109 Juxtaglomerular cell tumour. Hypertension and hypokalemia resolve after surgery. B Fig.108 Juxtaglomerular cell tumour. JGCT is histologically made of sheets of polygonal or spindled tumour cells with central round regular nuclei. distinct cell borders and abundant granular eosinophilic cytoplasm staining for the Bowie stain. Ultrastructural features include abundant rough endoplasmic reticulum. Investigation discloses high plasma renin activity. Immunohistochemistry with antibody to renin shows a diffusely positive reaction in juxtaglomerular cell tumour. Tumour cells are immunoreactive for renin. Juxtaglomerular cell tumour 73 . tumours present with a complex vascular hemangiopericytic pattern. Renin expression in some cells. prominent tubular elements either neoplastic or entrapped are also present. Macroscopy and histopathology JGCT is solid. Fig. well-circumscribed and yellow-tan. actin.

A Well circumscribed tumour composed of spindle cells in a basophilic matrix. About half the patients who have one renomedullary interstitial cell tumour have more than one. 74 Tumours of the kidney . C Fig.N. B Note deposits of amyloid.110 Renomedullary interstitial cell tumour forms a white nodule in a medullary pyramid.Renomedullary interstitial cell tumour J. 1. Eble ICD-O code 8966/0 Renomedullary interstitial cell tumours are common autopsy findings in adults {2161. They are asymptomatic and while renomedullary interstitial cells play a role in regulation of blood pressure. Interlacing bundles of delicate fibers usually are present. A B Fig. The renomedullary interstitial cells are small stellate or polygonal cells in a background of loose faintly basophilic stroma reminiscent of renal medullary stroma. Some renomedullary interstitial cell tumours contain deposits of amyloid. renal medullary tubules often are entrapped in the matrix. In these. Microscopically. renomedullary interstitial cell tumours have no clear influence on blood pressure. renomedullary interstitial cell tumours are seen to contain only small amounts of collagen.2163. the delicacy of the stroma is lost and irregular eosinophilic deposits of amyloid are present within the nodule. 1. they are larger {1604} and can form polypoid masses protruding into the renal pelvic cavity {896}. At the periphery.2783}. They are present in nearly 50% of men and women. Rarely.111 Renomedullary interstitial cell tumour. Almost all renomedullary interstitial cell tumours are 1-5 mm in diameter and appear as white or pale grey nodules within a renal medullary pyramid. C This example is sparsely cellular and composed of interlacing bands of nondescript spindle cells.

weight loss. 2424}. and devoid of Verocay bodies {2839}. Renomedullary interstitial cell tumour / Intrarenal schwannoma / Solitary fibrous tumour 75 . pelvis 28%. A haemangiopericytoma-like growth pattern is typically seen. hilum 28%.2778}. and abdominal or flank pain are common findings. Immunostaining for CD34.2424. 33%. The tumours are grossly well-circumscribed masses arising in the renal parenchyma. Malaise. Its occurrence in the kidney is very rare. renal schwannoma is composed of spindle cells often arranged in a palisading fashion (Antoni A pattern) and less cellular loosely textured tumour areas (Antoni B) {2424}. Haphazard proliferation of uniform spindle cells with strong immunoreactvity for CD34. Microscopically. They are variable in cellularity. A palpable abdominal mass is frequently present.112 Solitary fibrous tumour. fever. 1. storiform. Patients have nonspecific symptoms and signs. consisting of a mixture of haphazard. with hypercellular areas composed exclusively or predominantly of Antoni A tissue.7cm) in diameter and vary in colour from tan to yellow {1167. Alvarado-Cabrero ICD-O code 9560/0 Schwannoma is a common. Fig. 4 to 16cm (mean 9. or short fascicular arrangements of bland spindle cells and less cellular dense collagenous bands. Solitary fibrous tumour T.2424}.2460}. with only eighteen reported cases {73. Distribution of the 18 renal schwannomas was as follows: parenchyma. benign tumour of peripheral and auditory nerves {723}. Hematuria may also be present {73. sometimes lobulated.Intrarenal schwannoma I. Some tumours display the histologic features of cellular schwannomas.2653}. Tumours are well circumscribed. Hasegawa ICD-O code 8815/0 The lesion may be clinically confused with renal cell carcinoma or sarcoma because of its large size by physical examination and radiographic studies as well as the frequent presence of painless hematuria {1595.1585. rounded masses. bcl-2 and CD99 confirms the diagnosis. capsule 11% {73.

The cytoplasm may be eosinophilic or clear. low cuboidal. Clinical features Cystic nephroma presents as a mass and cannot be distinguished radiographically from other cystic neoplasms.Cystic nephroma S. Pleuropulmonary blastoma is a very rare paediatric tumour associated with cystic nephroma in the same patient and in other family members {1175}. The septa may contain clusters of mature tubules. Bonsib Definition Cystic nephroma is a benign cystic neoplasm composed of epithelial and stromal elements. 1. No solid areas or necrosis is present. Rarely. lesion may be focal or replace the entire kidney. B Cellular details of single cell layer composed of hobnail epithelium. A The tumour consists of small and large cysts.113 Cystic nephroma. or hobnail epithelium. Macroscopy Cystic nephroma is an encapsulated well-demarcated tumour composed entirely of cysts and cyst septa. A Cystic nephroma composed entirely of cysts and septae. The cysts contain serosanginous fluid that can occasionally appear haemorrhagic. ICD-O code 8959/0 Epidemiology Typically. 1. a predominantly intrapelvic presentation occurs {1411}.M. The A B Fig. The fibrous septa may be paucicellular or cellular resembling ovarian stroma. Histopathology The cysts are lined by a single layer of flattened. . A 76 Tumours of the kidney B Fig.114 Cystic nephroma. B The tumour is sharply demarcated from an otherwise normal kidney. cystic nephroma presents after age 30 and has an 8:1 female to male ratio.

25% are incidental findings. Histories of estrogen therapy are common. Urothelium.115 Mixed epithelial and stromal tumour. frequently herniating into the renal pelvic cavity. which may be hyperplastic. Clinical features There is a 6:1 predominance of women over men {35}. These varied elements often are present intermingled in the same area of the tumour. Fig. A B Fig. Epithelium with müllerian characteristics has also been described {205}. The tumours are typically composed of multiple cysts and solid areas. The microcysts and tubules are lined by flattened. and tubules. Macroscopy The tumours often arise centrally in the kidney and grow as expansile masses. cuboidal. to densely packed clusters of microcysts.N.Mixed epithelial and stromal tumour J. Fig. The architecture of the microcysts is varied and ranges from simple microcysts with abundant stroma between them. which sometimes forms small papillary tufts. Histopathology These are complex tumours composed of large cysts.116 Mixed epithelial and stromal tumour. or vacuolated. A Predominantly solid mass with scattered cysts.117 Mixed epithelial and stromal tumour forming spatulate papillae. 1. The largest cysts are lined by columnar and cuboidal epithelium. Synonyms Some authors have applied other names (cystic hamartoma of renal pelvis or adult mesoblastic nephroma) but the name "mixed epithelial and stromal tumour" best captures its nature {2035}. Mitotic figures and atypical nuclei have not been reported. Their cytoplasm ranges from clear to pale. The stroma consists of a variably cellular population of spindle cells with plump nuclei and abundant cytoplasm. Note fat cells in stroma. Densely collagenous stroma is common and fat is occasionally present. Surgery has been curative in all cases. or columnar cells. Presenting symptoms include flank pain. to complex branching channels which may be dilated. Areas of myxoid stroma and fascicles of smooth muscle cells may be prominent. 1. B Note glancing inner surface of the cystic tumour. microcysts. Cystic nephroma / Mixedepithelial and stromal tumour 77 . 1. Eble Definition Mixed epithelial and stromal tumour is a complex renal neoplasm composed of a mixture of stromal and epithelial elements. All have been adults and the mean age is perimenopausal (46 years). eosinophilic. may also line some portion of the cysts. Large tumour attached to the renal pelvis. haematuria or symptoms of urinary tract infection.

A Complex branching tubules in a spindle cell stroma with smooth muscle differentiation. Genetics Little is known of the genetics of these tumours except that they lack the translocation characteristic of cellular congenital mesoblastic nephroma {2073}. 1.A B Fig. Immunoprofile Immunohistochemistry shows that the spindle cells. which look like smooth muscle have strong reactions with antibodies to actins and to desmin. 78 Tumours of the kidney . The epithelial elements react with antibodies to a variety of cytokeratins and often vimentin.118 Mixed epithelial and stromal tumour. They occasionally react with antibody to estrogen receptor. The nuclei of the spindle cells also frequent- ly react with antibodies to estrogen and progesterone receptors {35}. B Cysts and small tubular structures resembling nephrogenic adenoma.

Argani M.2) and epithelial membrane antigen.119 Synovial sarcoma of the kidney.18)(p11. frequently reactive for CD99 but desmin and muscle specific actin are negative. and appear to be entrapped native renal tubules. A B C Fig. The tumour cells are often negative or only focally positive for cytokeratins (AE1/AE3. Areas of solid aggregation or fascicles of the tumour cells alternating with hypocellular myxoid tissues. B The cysts are lined by hobnail epithelium with abundant eosinophilic cytoplasm representing entrapped dilated tubules. A Note prominent cystic change. Rhabdoid cells in the tumour have been recently described {1253}. together with areas displaying a prominent haemangiopericytoma-like pattern. may be found.6:1).Synovial sarcoma of the kidney J. C Higher magnification shows monomorphic small spindle cells. or CAM 5. Cysts are lined by mitotically inactive polygonal eosinophilic cells with apically located nuclei ("hobnailed epithelium"). but multiple areas of haemorrhage. but the epithelial linSynovial sarcoma of the kidney 79 . Localization Tumour equally involves either kidney. 1. Histopathology Tumours are typically mitotically active.Y.R. which may be extensively dilated. Macroscopy Most of the tumours are solid. symptom in more than half of cases.120 Renal synovial sarcoma. but no bilateral tumours were identified. necrosis and cyst formation can be observed on gross examination. Synonyms and historical annotation A subset of previously described embryonal sarcoma of the kidney is now recognized to be primary renal SS {112}. with monomorphic plump spindle cells and indistinct cell borders growing in short. Immunoprofile The tumour cells are consistently immunoreactive with vimentin and BCL2. Ro K. Ladanyi Definition Synovial sarcoma (SS) of the kidney is a spindle cell neoplasm that infrequently displays epithelial differentiation and is characterized by a specific translocation. 1. intersecting fascicles or in solid sheets. Kim P. with a mean of 35 years and shows a slight male predilection (1. t(X.q11). ICD-O code 9040/3 Epidemiology Age and sex distribution Renal synovial sarcoma occurs in an age range 12-59 years.2. Clinical features Symptoms and signs Flank or abdominal pain with or without abdominal distension is the presenting Fig.

In contrast to soft tissue synovial sarcoma where the SYT-SSX1 gene fusion is more common than the alternative SYT-SSX2 form {1422}. positive control.18) (p11.negative control. 1. Prognosis and predictive factors Prognostic data are limited.Fig. the majority of renal synovial sarcomas have so far demonstrated the SYT-SSX2 gene fusion {112. Molecularly confirmed primary renal synovial sarcomas have demonstrated the characteristic SYT-SSX gene fusion {112. this tendency is also consistent with the predominance of monophasic spindled morphology of these tumours in the kidney and the rarity of biphasic histology.1379}. 80 Tumours of the kidney . 1316. molecular size marker. synovial sarcomas.1316}. Genetics Synovial sarcoma is cytogenetically char- acterized by the translocation t(X.122 Synovial sarcoma of the kidney. ing cells of the cysts are consistently highlighted by these markers {112. M.1316.SSX4) on chromosome X. In soft tissue synovial sarcomas. 3 and 4.SS X2. the SYT-SSX2 form of the gene fusion is strongly correlated with monophasic histology {1422}. SYT-SSX fusion transcripts demonstrated by RT-PCR.2) generating a fusion between the SYT gene on chromosome 18 and one member of the SSX family gene(SSX1. however recurrence is common. some have responded to chemotherapy.2/q11. Fig.121 Synovial sarcoma of the kidney. 2. 1.1. Immunoexpression of CD99 in the synovial sarcoma of the kidney.1379}.

2174}.2560}. and has a soft to moderately firm consistency. Clinical features The most common mode of presentation is abdominal pain.Renal carcinoid tumour L. Somatic genetics Only a few tumours have been studied by genetic methods {677. Tumour spread and staging Capsular invasion and/or renal vein involvement (pT3) has been reported.125 Renal carcinoid.759. 1690.1180.2688}. {202. 49 years. Somatostatin receptor scintigraphy (pentetreotide scan) is of adjunct value in staging and surveillance for the development of recurrent or metastatic disease {1662}.203.R. Fig. whereas necrosis is uncommon {203.2878}. lobulated and bulging appearance. lobulated tumour bulging from the central region close to the isthmus. Macroscopy Renal carcinoid is a solitary tumour with a well circumscribed. Cut surface is homogeneous and yellow-tan. There is no sex predilection. Histopathology Renal carcinoid displays the typical histologic features of carcinoids in other organs of the body. Bégin Definition A well differentiated neuroendocrine neoplasm arising within the kidney.2150. 1. A Trabecular pattern. beige-white or red-brown. median. Presentation is most common in the fourth to seventh decades.2463.903. 81 . B Tumour cell expression of synaptophysin. 51 years). Prognosis The clinical outcome is difficult to predict and a significant proportion of patients with metastatic disease have a protracted clinical course. 677.1764.124 Renal carcinoid.1819. only about 50 cases having been reported and there appears to be an association with horseshoe kidney {202. The appearance is homogeneous or may depict focal haemorrhage. CT scan.123 Renal carcinoid arising in a horseshoe kidney. Immunoprofile The immunohistochemical profile is similar to that of carcinoid tumours elsewhere. Carcinoid syndrome symptoms are uncommon (<10%) {1006. A B Renal carcinoid tumour Fig. The tumour is yellow-tan. 1. including a range from 13-79 years (mean.1764.2150}. 1.1662. ICD-O code 8240/3 Epidemiology Primary renal carcinoid is very rare. or haematuria. Bisected (hemi)nephrectomy specimen (from a horseshoe kidney) reveals a well circumscribed. Computed tomography usually reveals a circumscribed and solid mass with an occasional cystic component or calcification. mass. Horseshoe renal malformation.903. Immunoreactivity for prostatic acid phosphatase (PAP) has been documented in at least five tumours {202. 2150. 2688}. calcification and cystic changes. Fig.903.203.

1658. CD56 (NCam). Guillou et al. often extending into renal sinus adipose tissue. Guillou Definition A poorly-differentiated epithelial neoplasm showing neuroendocrine differentiation.2601}.1735. and tumour necrosis often extensive and accompanied with perivascular DNA deposition (Azzopardi phenomenon). synaptophysin.1658. Histopathology Morphologically. Most patients present with large and locally aggressive tumours. vascular tumour emboli common.1326. At least.1326.2601}. 75% of patients die of their disease within one year {727. centrally located.1658. nests and trabecula of apparently poorly-differentiated small.Neuroendocrine carcinoma of the kidney L. A concomitant urothelial carcinoma is common {727.1735}.2601}. gritty and necrotic renal mass. Their cytoplasm is hardly visible on HE sections.126 Small cell carcinoma of the kidney.971. necrotic tumour with renal pelvis invasion. A Large.971. Mitoses are numerous.971. These cells show characteristic hyperchromatic nuclei with stippled chromatin and inconspicuous nucleoli.2601} regardless of treatment. 727. Regional lymph nodes and distant metastases are common {368. round to fusiform cells separated by sparse intervening stroma. Prognosis and predictive factors The prognosis is poor and stage dependent. 82 Tumours of the kidney . {971} B.C Tumour cells show scant cytoplasm and granular chromatin with inconspicuous nucleoli.5 to 23 cm (median: 8 cm) {368. and neurone specific enolase {727. whitish.1658}. neuroendocrine carcinoma of the kidney occurs in adults (average age: 60 years) with no sex predilection.1658. Note nuclear molding and numerous mitoses. Tumours range in size from 2. 971. tumour cells show dot-like cytoplasmic staining with cytokeratins and are variably positive for neuroendocrine markers including chromogranin A. the tumour is composed of sheets.971.971. often surrounding the pelvicaliceal cavities.1658}. From L. B C Fig. The tumour presents as a soft.971. Macroscopy Most neuroendocrine carcinomas of the kidney are located close to the renal pelvis.727. ICD-O code 8246/3 Epidemiology Accounts for much less than 1% of all epithelial renal malignancies. 1.1735. Clinical features Abdominal pain and gross haematuria are the most frequent clinical symptoms {727. often extending into perirenal adipose tissue at diagnosis {368. 1735.1326. A Immunoprofile Immunohistochemically.

Neuroendocrine carcinoma of the kidney / Primitive neuroectodermal tumour (Ewing sarcoma) 83 . The mean age was 27 years with a median age of 21 years. flank pain and gross hematuria were the most common presenting symptoms. characterized by a translocation resulting in a fusion transcript of the EWS gene and ETS-related family of oncogenes. The cells are relatively monotonous polygonal cells whose appearance is dominated by a hyperchromatic rounded nucleus. A capsule or pseudocapsule was described in a minority of tumours.2124}. A palpable abdominal or flank mass was detected in less than 25% of cases. B Renal PNET.P. inhomogeneous mass often replacing almost the entire kidney was the common computed tomographic appearance {630}. weight loss and bone pain were other less frequent manifestations. Interspersed smaller "dark" cells 9260/3 9364/3 Epidemiology This neoplasm is rare {2009. 1. Note sheet-like growth pattern and rosettes. hepatic and bony metastases were noted at presentation in 10% of patients {385}. Clinical features Signs and symptoms Abdominal pain of recent (weeks) or sudden onset. There was a predilection for males (21 males. Cross-sec- B Fig. Dehner Definition A malignant tumour composed of small uniform round cells. Fever. A finely dispersed chromatin and a micronucleolus in some cases are the nuclear characteristics. A Imaging A sizable. Histopathology The tumour in the kidney is no different than the more common counterpart in soft tissues.127 A PNET of the kidney. ICD-O codes Ewing sarcoma Peripheral neuroectodermal tumour tional features included a greyish-tan to white lobulated surface with interspersed areas of haemorrhage and necrosis. 14 females). Areas of high and low intensity reflected the common presence of haemorrhage and necrosis in resected specimen. Macroscopy A mass measuring in excess of 10 cm in diameter with replacement of the kidney and weighing 1 kg or more in some cases served to characterize these neoplasms as a group {1225}. Pulmonary. A review of 35 cases of renal PNET-EWS revealed an age range from 4-69 years which is somewhat wider than that recorded for this tumour in the bone and soft tissues.Primitive neuroectodermal tumour (Ewing sarcoma) L.

Variant translocations with EWS are those with other ETS-related oncogenes: (21q22). The staining pattern for vimentin and cytokeratin may be perinuclear or Golgi zone punctate reactivity.128 PNET of the kidney. Extensive renal sinus invasion may simulate a pelvic tumour. Immunoprofile The basic immunophenotype of PNETEWS. (7p22). synaptophysin.neuron specific enolase. NEC= neuroendocrine carcinoma. "salt and pepper" chromatin. Aggressive multidrug chemotherapy has resulted in an improvement in the clinical outcome {525}. Table 1. Approximately 20% of cases also express pan-cytokeratin. Because most neuroblastomas arise from the adrenal.representing tumour cells undergoing pyknosis are prominent in some cases. 1. a rim of clear cytoplasm and discrete cell membranes are often apparent in well-fixed tumours without extensive degenerative changes. tive neural tissue defines neuroblastomas.M. neurofibrillary stroma. VIM PNET-EWS NB Carcinoid NEC NHL Blastemal WT ________ Abbreviations: CK +/– – + + – + CHR +/– + + + – – SYN +/– + + + – – NSE + + + + – +/– CD99 + – – – +* – CD45 – – – – + – WT-1 – – – – – + CD117 + + – – – + + – – – + + PNET-EWS = primitive neuroectodermal tumour / Ewing sarcoma. is the expression of vimentin and the surface antigen of the MIC2 gene. CK = cytokeratin. Far more frequently. and chromogranin. Somatic genetics Virtually all of the recently reported PNETEWSs have had the t(11. Fig. (17q12) and (2q33). regardless of the primary site.2124}. Prognosis Pathologic stage is the major determinant in the prognosis of PNET-EWS regardless of the primary site. VIM = vimentin. Though the nuclear to cytoplasmic ratio is high. NSE . and embryonal cells with round nuclei containing granular. Preoperative determination of urine catecholamine excretion is helpful in diagnosis of neuroblastoma but may not exclude nephroblastomas with neural elements {2273}. adrenal neuroblastomas invade the adjacent kidney. CD99 (O13) or HBA-71. SYN = synaptophysin. which contain Homer Wright rosettes. CHR = chromogranin. NHL= non-Hodgkin lymphoma. Neuroblastoma ICD-O code 9500/3 this occurs in approximately five per cent of cases {2375}. CD99 expression. 84 Tumours of the kidney .q12) translocation with the fusion transcript between the EWS gene (22q12) and the ETS-related oncogene. Pure intrarenal lesions hypothetically arise from either adrenal rests or intrarenal sympathetic tissue {2385}. WT = Wilms tumour.22)(q24. The presence of clear cytoplasm is often associated with abundant glycogen as demonstrated by diastase sensitive PAS-positivity. Important positive indicators of neuronal differentiation include neuronspecific enolase. Parham Neuroblastomas arising as a true intrarenal mass are extremely rare.12 Immunohistochemical differentiation of neuroectodermal tumours from other tumours with similar microscopic features. Mitotic figures may be numerous. The presence of primi- D. S100 protein. NB= neuroblastoma. FLI1 (11q24) {1627. * CD99 is expressed by lymphoblastic lymphoma. those affecting the kidney predominate in the superior pole. only six cases were identified in the National Wilms Tumour Study Pathology Centre in 1993 {2225}.

Marx S. Clinical features Common symptoms are flank or abdominal pain. 1. and CD56 are consistently strong in virtually all tumour cells.622.2097.2696}.2382}. hypertension.Paraganglioma / Phaeochromocytoma Ph. calcifications and tumoral thrombus formation in the renal vein may occur {2677. Etiology PRL arising in transplanted kidneys are usually EBV-associated monomorphic or polymorphic B-cell lymphoproliferations of donor origin and related to iatrogenic immunosuppression {439. Intravascular large B-cell lymphoma almost always affects the kidneys but may cause no macroscopic change {2819}.2760}. The cut surface is grey. primary lymphomas may present as a mass lesion and regarded clinically as a renal epithelial neoplasm and treated by nephrectomy.626.U.1695.1354. renal insufficiency. Neuroblastoma / Paraganglioma / Lymphomas 85 . This is due to oxidation of chromaffin substances. Dissemination following the diagnosis of PRL is common. weight loss.1267. containing blood vessels and sustentacular cells. The cut surface is usually homogeneous. Complications are renal failure {750} and paraneoplastic hypercalcemia {2676}.2833}. Secondary renal lymphomas (SRL) affect the kidney as the second most common site for metastasis {2284}.2097}.2097. have been described. The colour of the parenchyma often rapidly turns brown when exposed to air.1881.537. However. constitutes the single most frequent type of PRL and SRL {448. or acute renal failure {448. cystic changes. both Hodgkin disease and non-Hodgkin lymphoma. The architecture is characterized by cell clusters ("Zellballen") surrounded by a net- work of fine collagenous septa.2647}.M. Most tumours are small. but necrosis. often well vascularized. dissemination to extrarenal sites is common and confers a bad prognosis as well {622}. Lymphomas A. In the non-transplant patients. Most present (48%) in advanced stage lymphoma {1267}. The immunoreactions for synaptophysin. Histopathology There are three patterns of renal involvement. haemorrhage. including catecholamines.2647. including its variants. Heitz ICD-O codes Paraganglioma Pheochromocytoma 8680/1 8700/0 A very small number of tumours have been described in the kidney {595. Macroscopy Nephrectomy specimens in primary or secondary lymphoma show single or multifocal nodules (eventually associated with hydronephrosis) or diffuse renal enlargment. 755.129 Lymphoma. Diffuse large B-cell lymphoma.2696}.1426}. chromogranin A. haematuria.839. In secondary lymphoma.750. The most common is diffuse involvement with lymphoma cells permeating between the native nephron structures resulting in marked organ enlargement. Modern radiochemotherapy has improved survival and renal functional compromise {2097. Prognosis and predictive factors Secondary renal lymphoma usually indicates stage IV disease with dismal prognosis {327. Fig. firm and pale. The least common pattern is the intravascular form where lymphoma cells fill all vascular components. Bonsib Definition Primary renal lymphoma is a lymphoma without evidence of systemic involvement. Almost every histological lymphoma subtype may be encountered. fever. Epidemiology Less than 100 cases of primary renal lymphomas. The diagnosis requires renal and bone marrow biopsy and thoraco-abdominal CT {2477}. Protein S-100 highlights tumour cells and sustentacular cells. post-transplant lymphoproliferative disorders are the most frequently encountered disorder today. In PRL. bilateral involvement is frequent (10% to 30%) {13. 2097. It is 30x more common than PRL {374. The second pattern is formation of one or more tumour masses.537}.2408.

a complete radiologic work-up must show no evidence of other lesions. 86 Tumours of the kidney . B High magnification illustrating the plasma cell proliferation which is characterized by a mixture of both mature and immature plasma cells. may rarely be the site of origin of a solitary (primary) extraosseous PC {1266.Plasmacytoma A. 1. The other myeloma associated criteria are also absent.2933}. however. The bone marrow must show no evidence of plasmacytosis and/or plasma cell monoclonality. A B C Fig. The kidney. Orazi Plasmacytoma (PC) of the kidney most often occurs as a manifestation of disseminated multiple myeloma. PC of the kidney is histologically indistinguishable from plasmacytoma occurring elsewhere. To qualify as a primary PC. A The low power photomicrograph shows a well demarked nodular lesion surrounded by unremarkable kidney parenchyma.130 Plasmacytoma involving the kidney in a patient with disseminated multiple myeloma.

Plasmacytoma / Leukaemia / Germ cell tumours 87 .Leukaemia A.580.1986.1728. 1.989}. or chronic lymphocytic leukaemia has rarely been reported in the literature {989}.A. megakaryoblastic leukaemia. Reported cases have involved the renal parenchyma or the renal hilus and have been indistinguishable from teratomas of the gonads. Most of the cases in the literature {1019. Germ cell tumours I. 1135} are metastases from testicular germ cell tumours {1168. The wide range of differentiation in nephroblastoma can resemble teratoma. Fig. MS may occur "de novo" or simultaneously with acute myeloid leukemia.2878}. Orazi Interstitial infiltration of leukaemic cells without a nodular mass is best referred to as extramedullary leukaemia in kidney. {6.131 Myeloid sarcoma in the kidney showing multiple haemorrhagic fleshy nodules. Sesterhenn Primary renal choriocarcinomas have rarely been reported and are difficult to distinguish from high grade urothelial carcinomas with syncytiotrophoblasts. Reports of teratomas of the kidney are very rare.1804}. Fig. It may represent the first manifestation of leukaemia relapse in a previously treated patient.138. or myelodysplastic syndrome {154. Myeloid sarcoma (MS) is a neoplastic proliferation of myeloblasts or immature myeloid cells forming a mass in an extramedullary site. 1. 916. a tumour composed of myeloblasts and promyelocytes {154}. Diffuse infiltration of the kidney secondary to acute myeloid and lymphoblastic leukaemias. The malignant proliferation consists of a mixture of promyelocytes and myeloblasts.132 Myeloid sarcoma in the kidney. The commonest type of myeloid sarcoma occurring in the kidney is known as granulocytic sarcoma. myeloproliferative dis- order.

The origin of bladder cancer is multifactorial. Improvements in early detection have made reproducible grading and staging important criteria for clinical management and prognosis.80%.000 new cases per year worldwide. occupational exposure and chronic Schistosoma cystitis. . with five-year survival rates of 60 .CHAPTER 2 Tumours of the Urinary System With approximately 260. Other etiological factors include analgesic abuse. Progress in the early detection and treatment of bladder cancer has improved the prognosis. with tobacco smoking as the principal cause in most countries. Urothelial carcinomas are the most frequent and important tumour type. tumours of the urinary system contribute significantly to the overall human cancer burden.

low grade Non-invasive papillary urothelial neoplasm of low malignant potential Urothelial papilloma Inverted urothelial papilloma Squamous neoplasms Squamous cell carcinoma Verrucous carcinoma Squamous cell papilloma Glandular neoplasms Adenocarcinoma Enteric Mucinous Signet-ring cell Clear cell Villous adenoma 8120/31 Neuroendocrine tumours Small cell carcinoma Carcinoid Paraganglioma Melanocytic tumours Malignant melanoma Nevus Mesenchymal tumours Rhabdomyosarcoma Leiomyosarcoma Angiosarcoma Osteosarcoma Malignant fibrous histiocytoma Leiomyoma Haemangioma Other Haematopoietic and lymphoid tumours Lymphoma Plasmacytoma Miscellaneous tumours Carcinoma of Skene.WHO histological classification of tumours of the urinary tract Urothelial tumours Infiltrating urothelial carcinoma with squamous differentiation with glandular differentiation with trophoblastic differentiation Nested Microcystic Micropapillary Lymphoepithelioma-like Lymphoma-like Plasmacytoid Sarcomatoid Giant cell Undifferentiated Non-invasive urothelial neoplasias Urothelial carcinoma in situ Non-invasive papillary urothelial carcinoma. high grade Non-invasive papillary urothelial carcinoma. 90 Tumours of the urinary system . /3 for malignant tumours.org). and /1 for borderline or uncertain behaviour. /2 for in situ carcinomas and grade III intraepithelial neoplasia. Behaviour is coded /0 for benign tumours. Cowper and Littre glands Metastatic tumours and tumours extending from other organs 8041/3 8240/3 8680/1 8720/3 8131/3 8082/3 8122/3 8031/3 8020/3 8120/2 8130/23 8130/21 8130/1 8120/0 8121/0 8900/3 8890/3 9120/3 9180/3 8830/3 8890/0 9120/0 9731/3 8070/3 8051/3 8052/0 8140/3 8480/3 8490/3 8310/3 8261/0 __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {808} and the Systematized Nomenclature of Medicine (http://snomed.

abdominal wall T4a Tumour invades prostate.org/tnm/ TNM classification of carcinomas of the renal pelvis and ureter TNM classification 1. or multiple lymph nodes. or multiple lymph nodes.2662}. none more than 5 cm in greatest dimension Metastasis in a lymph node more than 5 cm in greatest dimension N3 M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Grouping Stage 0a Stage 0is Stage I Stage II Stage III Stage IV Ta Tis T1 T2a. b T3a.uicc. 2 A help desk for specific questions about the TNM classification is available at http://www.2 T – Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: "flat tumour" T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate.uicc. uterus.TNM classification of carcinomas of the urinary bladder TNM classification 1. N3 Any N M0 M0 M0 M0 M0 M0 M0 M0 M1 __________ 1 {944.2 T – Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ T1 T2 T3 Tumour invades subepithelial connective tissue Tumour invades muscularis (Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into periureteric fat Tumour invades adjacent organs or through the kidney into perinephric fat N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension. vagina. uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 N2 Metastasis in a single lymph node 2 cm or less in greatest dimension Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension. N2.org/tnm/ 91 . N3 Any N M0 M0 M0 M0 M0 M0 M0 M1 __________ 1 {944. N2. b T4a T4b Any T Any T N0 N0 N0 N0 N0 N0 N0 N1. none more than 5 cm in greatest dimension Metastasis in a lymph node more than 5 cm in greatest dimension N3 M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Grouping Stage 0a Stage 0is Stage I Stage II Stage III Stage IV T4 N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension Ta Tis T1 T2 T3 T4 Any T Any T N0 N0 N0 N0 N0 N0 N1.2662}. 2 A help desk for specific questions about the TNM classification is available at http://www. pelvic wall.

bladder neck (extra.2 T – Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension N2 Metastasis in a single lymph node more than 2 cm in greatest dimension. beyond prostatic capsule. T2 T3 T4 Any T Any T N0 N0 N0 N0 N0 N0 N1 N0. involvement of prostatic ducts T1 T2 T3 T4 Tumour invades subepithelial connective tissue Tumour invades any of the following: prostatic stroma.org/tnm/ 92 Tumours of the urinary system . beyond prostatic capsule. prostate.prostatic extension) Tumour invades other adjacent organs (invasion of bladder) Stage I Stage II Stage III Stage IV Ta Tis Tis pu Tis pd T1 T2 T1.uicc. periurethral muscle T3 Tumour invades any of the following: corpus cavernosum. N1 N2 Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1 __________ 1 {944. or multiple lymph nodes M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Grouping Stage 0a Stage 0is Urethra (male and female) Ta Non-invasive papillary. involvement of prostatic urethra Tis pd Carcinoma in situ. N1 N0. anterior vagina.2662}. polypoid.TNM classification of carcinomas of the urethra TNM classification 1. or verrucous carcinoma Tis Carcinoma in situ T1 Tumour invades subepithelial connective tissue T2 Tumour invades any of the following: corpus spongiosum. periurethral muscle Tumour invades any of the following: corpus cavernosum. corpus spongiosum. bladder neck T4 Tumour invades other adjacent organs Urothelial carcinoma of prostate (prostatic urethra) Tis pu Carcinoma in situ. 2 A help desk for specific questions about the TNM classification is available at http://www.

in other regions (e.9% of all bladder tumours worldwide {2016}. France or Italy. and white population of Connecticut (USA) – 8. derived from the uroepithelium. Schmitz-Dräger B.5% and 1.8% of all bladder cancers in men and women respectively.01 Estimates of the age-standardized incidence rates of bladder cancer in males.E. Jones P. Fig. among all registries included into the 8th volume of "Cancer Incidence in Five Continents" {2016} urothelial carcinoma constitutes 84% of bladder cancer in males and 79% in females. which constitutes more than 90% of bladder cancer cases in USA. Eastern and Northern Europe.0/105.1/105. Cairns R. Cancer of the urinary bladder accounts for about 3.2% of all cancers worldwide and is considerably more common in males than in females (ratio worldwide is about 3. and Mallorca (Spain) – 39. Infiltrating urothelial carcinoma 93 .5:1) {2014}. The excess of risk is observed also with increasing intensity of smoking (number of cigarettes per day). Scotland (UK) – 8. Tis. Hartmann B.5/105. North America and Australia {2016}. The risk of bladder cancer in smokers is 2-6 fold that of non-smokers {313.391. The highest rates in females were noted in Harare (Zimbabwe) – 8. It is estimated that the risk of bladder cancer attributed to tobacco smoking is 66% for men and 30% for women {1158}.g. Simon M. i. Amin J.000 new cases occurring each year in men and 76. Helpap A.1/105.e.000 in women {749}. some studies indicate higher risk in women than in men at the equivalent level of exposure {391}. It is estimated that approximately 70-80% of patients with newly diagnosed bladder cancer present with non-invasive or early invasive (i.G. Lopez-Beltran G. Sauter T. Tyczynski Definition Infiltrating urothelial carcinoma is defined as a urothelial tumour that invades beyond the basement membrane. 1877}. with an estimated 260. Gasser A. North Western England (UK) – 8. From Globocan 2000 {749}. 2. Tamboli M.A. Asia) the relative frequency of urothelial carcinoma of the bladder is lower. Cordon-Cardo P.B.Infiltrating urothelial carcinoma A.1% and 2. The increase of risk with the increasing duration and intensity of smoking is similar in both sexes {1158} but.e. In general. Ayala P.0/105. The most common type of bladder cancer in developed countries is urothelial carcinoma. Africa. reaching maximum of about 3 for those smoking 40 or more cigarettes per day {313}. or T1). In both sexes. However. In all "Cancer Incidence in Five Continents" {2016} registries squamous cell carcinoma accounts for 1. squamous cell carcinoma and adenocarcinoma have much lower relative frequency.A. In general. Etiology of urothelial bladder cancer Risk factors There are several known and potential risk factors of bladder cancer. Knowles D.J. the highest incidence rates of bladder cancer are observed in Western Europe. Sidransky C. The highest incidence rates of bladder cancer in males in 1990s were observed in the following registries: Limburg (Belgium) – 42. and for those with the longest history of smoking (60 years or more) reaches approximately 6 in men and 5 in women {313}. the prevalence of bladder tumours in developed countries in approximately 6-times higher compared with that in developing countires. adjusted to the world standard age distribution (ASR). ICD-O code 8120/3 Synonym Transitional cell carcinoma. Epidemiology of urothelial bladder cancer Bladder cancer is the 7th most common cancer worldwide. Tobacco smoking Tobacco smoking is the major established risk factor of bladder cancer. The highest prevalence of bladder cancers in both males and females is observed in North America and in countries of the European Union {2084}. stage Ta. Adenocarcinoma of the bladder constitutes respectively 1. The risk increases with increasing duration of smoking.5/105 {2016}. Other types of bladder cancer.3/105. Genoa Province (Italy) – 41. Cigarette smoking and occupational exposure to aromatic amines are the most important among them {1877}.

Some authors suggested association between bladder cancer and urinary tract infections and urinary tract stones. who reported high rates of bladder cancer among men employed in the aniline dye industry {617}. The IARC currently classifies saccharin in group 3. The decrease of risk after cessation is similar in both sexes {391}. ureter and bladder. The above exposures have been classified into IARC Group-1 (carcinogenic to humans). mixtures or exposure circumstances associated with bladder cancer. and 15 years cessation tends to be approximately that of non-smokers {1158}.02 Relative frequency of major histological types of bladder tumours in females. It has been estimated that contact with occupational carcinogens causes up to 25% of all bladder tumours {2025}. Fig.2444}.4 to more than 6 {1150}. while no increase of risk was observed in ever smokers {2840}. Aluminium production 4-Aminobiphenyl Analgesic mixtures containing phenacetin Arsenic in drinking water Auramine manufacture Benzidine Chlornaphazine Coal gasification Coal-tar pitch Cyclophosphamide Magenta manufacture 2-Naphthylamine Rubber industry Schistosoma haematobium (infection) Tobacco smoke Coffee There is no clear evidence of carcinogenic effect of coffee or caffeine in experimental animals {1151}. Key evidence came from ecological studies in Chile and Taiwan (China) where large populations were exposed {1157}. A recent study showed increased risk of bladder cancer caused by coffee drinking only in never smokers. The resultant bladder tumours are usually squamous cells carcinomas. and possibly 1-naphthylamine.1150. The underlying mechanism may lead to chronic irritation of the bladder epithelium. Occupational exposure Bladder cancer is associated with a number of occupations or occupational exposures.M. treatment with cyclophosphamide has been reported to be associated with an increased risk of squamous cell carcinomas and sarcomas. Subsequent research among dyestuffs workers identified the aromatic amines benzidine and 2-naphthylamine. i. especially leiomyosarcomas {1150. Switzerland {1729} and Australia {1668}. cyclophosphamide. chlornaphazine is associated with the development of bladder cancer {2606}. Phenacetin Several epidemiological studies indicate that chronic abuse of analgesics containing phenacetin greatly enhance the risk of developing urothelial cancer of the renal pelvis. The most common presenting symptom of bladder cancer is painless gross hematuria which occurs in 85% of patients {2713}.The risk of bladder cancer goes down after stopping smoking. Similarly.460}. From D. as bladder carcinogens {1150}.01 Alphabetical list of agents. The relative risk has been estimated in the range of 2. Clinical features Signs and symptoms The type and severity of clinical signs and symptoms of infiltrating urothelial carcinoma depends on the extent and location of the tumour. Arsenic Several studies showed that use of drinking water containing chlorination byproducts or contaminated by arsenic may increase risk of bladder cancer {367. An IARC Monographs Working Group reviewed in 2004 the relevant epidemiological studies and concluded that arsenic in drinking-water is carcinogenic to humans (Group 1) and that there is sufficient evidence that it Table 2. not classifiable as to its carcinogenicity to humans {1155}. Subsequent clotting and ________ Compiled from the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Medicinal drugs The cytostatic agent. 94 Tumours of the urinary system . has long been associated with the development of leukemia and lymphoma. {2016}. 2577}.1117. Chronic infections Chronic cystitis caused by Schistosoma haematobium is an established cause of bladder cancer. The first such association was observed in 1895 by Rehn. 2. Most patients with urothelial tumours present with at least microscopic hematuria {1718}. but some epidemiological studies in humans showed elevated risk in coffee drinkers as compared with non-coffee drinkers. {1027}. Artificial sweeteners There is no convincing evidence that artificial sweeteners (such as saccharin) play a role in the etiology of bladder cancer {1877}. causes urinary bladder cancer.e. which may increase bladder cancer risk. Early cases have been reported from Scandanavia {253. In addition. Parkin et al. Glutathione S-transferase M1 (GSTM1) null status is associated with a modest increase in the risk of bladder cancer {700}.

Similar symptoms may be present in the case of extensive carcinoma in situ. Hydronephrosis may result but may go clinically unnoticed if obstruction develops slowly. A. In most institutions CT is used as a primary staging tool as it is more accessible and more cost effective than MRI. Bloody discharge from the urethra requires endoscopic examination and surgical resection if tumour is found. Tumours infiltrating the ureteral orifice may lead to hydronephrosis. Endoureteric sonographic evaluation of ureteral and renal pelvic neoplasms is technically feasible {1515}. However. Upper tract tumours occur in less than 10% of patients with bladder tumours. Rarely. A fraction of patients with T1 disease may be treated by repeat transurethral resection alone. In case of a single kidney or bilateral obstruction anuria and renal insufficiency result. Approximately two thirds of the tumours are located in the distal ureter {146}. In case of large tumours bladder capacity may be reduced resulting in frequency. Bladder (black) with tumour (white) protruding into the lumen. Imaging Various imaging modalities are used not A B C Fig. non-invasive.e. patients with extensive disease present with a palpable pelvic mass or lower extremity oedema. only for detection but also for staging of infiltrating urothelial carcinoma. which recently is also performed laparoscopically {879}. both CT and MRI scanning often fail to differentiate between post-transurethral resection oedema and tumour {168}. Primary infiltrating urothelial tumours of the urethra are rare. While IVU is reliable in diagnosing intraluminal processes in ureter. pelvis and – with lesser accuracy – in bladder. Infiltrating urothelial carcinoma 95 . computed tomography (CT) and magnetic resonance imaging (MRI). it is confirmed on cystoscopy. Microscopic hematuria may be the first clinical signs of infiltrating tumours of the renal pelvis and ureter and roughly half of the patients present with gross hematuria {94}. In case of advanced disease weight loss or abdominal or bone pain may be present due to metastases. Tumours located at the bladder neck or covering a large area of the bladder may lead to irritative symptoms. Unlike in other tumours diagnostic accuracy of positron emission tomography (PET) in patients with invasive carcinoma of the bladder is poor {1481}. Transurethral ultrasonography may increase accuracy to >95% for T2 and T3 bladder tumours {1357}. Standard treatment for upper tract tumours is nephroureterectomy including the ureteral orifice {25}. inexpensive and available in most institutions. intravenous urography (IVU). However. In case of suspected upper urinary tract tumour radiological imaging (intravenous urogram or computed tomography) or endoscopic examination is advised {1405}. has increasingly been replaced by CT and MRI {96}. 2. in case of extensive disease most patients are candidates for potentially curative treatment. Sensitivity reaches only 63%. obesity of the patient or postoperative changes. However.B Ultrasound images of a solid bladder tumour. Enhanced computing methods bear the potential to improve accuracy by transforming data into three dimensional images allowing for “virtual” endoscopy {765}.painful micturition may occur. MRI appears to be somewhat better to assess the depth of intramural invasion and extravesical tumour growth but does not exceed 83% {2454}. Transabdominal ultrasonography of the bladder is quick. Occasionally. There is a high false negative rate for ultrasound examination because of tumour location. Conversely. recurrent tumour is found in the urethral stump after cystectomy. therefore.03 Infiltrative urothelial carcinoma. In addition IVU misses many extraluminal pathologic processes (such as renal mass) and. it fails to detect the extent of extramural tumour. which is considered a poor prognostic sign {999}. Although diagnosis of a bladder neoplasm may sometimes be suspected on ultrasound or computed tomography scan. Spiral CT has increased accuracy as breathing artefacts are diminished. Understaging of lymph node metastases in up to 40% and overstaging 6% of the cases are the major causes of error. staging accuracy is less than 70% for infiltrating bladder tumours {598}. Histological diagnosis is secured by resecting the tumour deep into the muscular layer of the bladder wall. They include ultrasound. yet with a specificity of 99% {554}. urgency and frequency. C Multiple metastases (hot spots) of the bone. In case of blood clotting obstruction may be acute and lead to painful ureteral flank colic and can be mistaken for ureterolithiasis. as endoluminal sonography is invasive and examiner dependent it is not routinely used. approximately 15 % of patients with carcinoma in situ of the bladder present with prostatic urethral involvement {1907}. dysuria. Staging accuracy of CT has been described in the range of 55% for urothelial carcinoma in the urinary bladder {1997}. However. Iliac lymph nodes cannot be assessed reliably on ultrasound. i.

Re-biopsy 1-6 weeks after the primary resection is most often performed in large pTa and all pT1 tumours {411. Tumour infiltrating muscle is not equivalent to muscularis propria invasion as small slender fascicles of muscle are frequently present in lamina propria (muscularis mucosae) {2203}. Because of the coincidence of simultaneous bladder tumours cystoscopy of these patients is mandatory {99. Skeletal scintigraphy for the detection of bone metastases should be performed in symptomatic patients. The accuracy of imaging techniques (CT. Imaging procedures (CT. To identify simultaneous bladder tumours cystoscopy of these patients is mandatory {99. CT. C Invasive urothelial carcinoma with deep infiltration of the bladder wall. A Papillary and invasive bladder carcinoma.2402.1137}. The use of CT-guided needle biopsy of lymph nodes has been reported {239}.2864}.Tumour spread and staging Urinary bladder T category Cystoscopy provides a limited role in the staging process {468. MRI) are A B C D Fig. N category N-staging is performed by imaging techniques (CT.394. The role of intravenous pyelography for detecting simultaneous tumours of the upper urinary tract (UUT) and/or ureteral obstruction is controversial {63. In case of positive urine cytology without a visible lesion or evidence of upper urinary tract tumours random biopsies from different areas of the bladder wall are taken to detect Tis bladder cancer. Prostatic and urethral urothelial tumours T category T-staging of urothelial tumours of the prostate ducts or urethra is performed after biopsy or after radical surgery.1332. M category In muscle-invasive tumours lung X-ray and exclusion of liver metastases by imaging (ultrasound.e. MRI) may be of value {838. lymph node enlargement is highly predictive of metastatic disease. a potential therapeutic impact has been assigned to this procedure {2102.540. M-staging is recommended before cystectomy. 2746} has been investigated in numerous studies. MRI) or by lymph node dissection {542}.1085. solid. pT categorization in TURB allows for recognition of pT1 and pT2 disease but the definitive categorization requires examination of the cystectomy specimen. Upper urinary tract tumours T category T-staging of tumours of the upper urinary tract tumours is performed after radical surgery in the vast majority of cases or after endoscopical tumour resection. In T1 disease. N category N-staging is performed by imaging techniques (CT.1997. 96 Tumours of the urinary system . ulcerative gross type of carcinoma. 645. Imaging procedures (CT.2733}. sentinel lymph node resection or laparascopic lymph node dissection for N-staging are considered experimental {686. polypoid. MRI) may be helpful {771}. Specifically for meatal or distal urethral tumours the inguinal region must be considered. PET) for determining the T-category is limited {234.2323}. required. however.2387}. Transurethral resection (TURB) of all visible lesions down to the base is required for accurate assessment of depth of tumour invasion. M-staging in upper urinary tract tumours follows the same rules. The impact of additional random biopsies remains unclear {751}.1747. Nevertheless. Cystectomy specimen.04 Invasive urothelial carcinoma. Macroscopy Infiltrative carcinomas grossly span a range from papillary. sensitivity and specificity of these techniques remains limited. i. Bimanual palpation to diagnose organ-exceeding tumours has lost its impact. Modifications.2089}.319}. Furthermore. They may be solitary or multifocal. 2. nodular.2732. Pelvic lymph node dissection up to the aortic bifurcation represents the state-ofart procedure. MRI) and by lymph node dissection {1349.119}. M category Because of similarities with bladder tumours {552. M category In general. D Ulcerative carcinoma. MRI. M-staging in urothelial tumours of the prostate or urethra follows the same rules as in bladder tumours. The remaining mucosa may be nor- N category The impact of CT and MRI {352. B Invasive urothelial carcinoma with infiltration of the muscular bladder wall.2740.1050. ulcerative or transmural diffuse growth.2302}. Tumour infiltrating the adipose tissue is not always indicative of extravesical extension as fat may be normally present in all layers of the bladder wall {2069}. 2651.1750}.901}.

thermal and mechanical injury.2177. Mitotic figures are common. Retraction clefts are often present around the nests of carcinoma cells. The nucleus is typically pleomorphic and often has irregular contours with angular profiles. defined by the presence of intercellular bridges or keratinization. Occasionally. dense. 2. and in 44% of tumours of the renal pelvis {1554. It is important to be aware of this feature in order to avoid misinterpretation as vascular invasion. 2. Divergent differentiation frequently parallels high grade and high stage urothelial cancer.1798}.944}. with bizarre and multinuclear tumour cells {293}. These carcinomas are graded as low grade and high grade depending upon the degree of nuclear anaplasia and some architectural abnormalities {706. Most of pT1 cancers are papillary. a feature known as pseudosarcomatous stromal reaction {1555}. Foci of marked pleomorphism may be seen.05 Infiltrative urothelial carcinoma. Detailed histologic maps of urothelial carcinoma with squamous differentiation have shown that the proportion of the squamous component may vary considerably. Thermal artefact can also hamper the interpretation of muscularis propria invasion. In most cases. but seems to be an unfavourable prognostic A Fig. The clinical significance of squamous differentiation remains uncertain. marked inflammatory infiltrate obscuring neoplastic cells and inverted or broad front growth {78}. Nucleoli are highly variable in number and appearance with some cells containing single or multiple small nucleoli and others having large eosinophilic nucleoli.1552}. or single cells within the papillary cores and/or lamina propria. In larger nests. It is recommended that the extent of lamina propria invasion in pT1 tumours should be stated {706}.2177} and an estimate of the percentage of squamous component should be provided. Histopathology The histology of infiltrating urothelial carcinomas is variable {80. Recognition of invasion may be problematic because of tangential sectioning. clusters. mimicking vascular invasion. Its frequency increases with grade and stage {1554}. tumour cells within the retraction spaces. including urothelial carcinoma in situ {2177}. Some cases may show relatively bland cytology {2896}. The depth of lamina propria invasion is regarded as a prognostic parameter in pT1 cancer. The diagnosis of squamous cell carcinoma is reserved for pure lesions without any associated urothelial component. with numerous abnormal forms. The histology of infiltrative urothelial carcinoma has no specific features and shows infiltrating cohesive nests of cells with moderate to abundant amphophilic cytoplasm and large hyperchromatic nuclei. Virtually the whole spectrum of bladder cancer variants may be seen in variable proportions accompanying otherwise typical urothelial carcinoma. Neutrophils and eosinophils are rarely prominent. Infiltrating urothelial carcinoma 97 .2276}. A Early tumour invasion into papillary stalk (H&E).1637}. B Fig. CT image of a solid bladder tumour protruding into the lumen. whereas most pT2-T4 carcinomas are non-papillary and high grade. although it may be severe. 2655}. and should be reported {1554. Cytokeratin 14 and L1 antigen have been reported as immunohistochemical markers of squamous differentiation {1025. are expressed in urothelial carcinoma and not in squamous differentiation {2848}. The inflammation is usually mild to moderate and focal. even focally. Uroplakins. Tumours with any identifiable urothelial element are classified as urothelial carcinoma with squamous differentiation {1554. occurs in 21% of urothelial carcinomas of the bladder.293. The most important element in pathologic evaluation of urothelial cancer is recognition of the presence and extent of invasion {293}. and widespread. The invasive nests usually induce a desmoplastic stromal reaction which is occasionally pronounced and may mimic a malignant spindle cell component. In early invasive urothelial carcinomas (pT1). it portends a poor prognosis and has different therapeutic ramifications. the stroma contains a lymphocytic infiltrate with a variable number of plasma cells. and hence should be diagnosed as small cell carcinoma. Histologic variants Urothelial carcinoma has a propensity for divergent differentiation with the most common being squamous followed by glandular. foci of invasion are characterized by nests.06 Infiltrative urothelial carcinoma (stage T1). mucoid cytoplasmic inclusions may be present. palisading of nuclei may be seen at the edges of the nests. low or high grade.mal or erythematous which sometimes represents the microscopic areas of carcinoma in situ. with some cases having urothelial carcinoma in situ as the only urothelial component {2276}. Squamous differentiation may show basaloid or clear cell features. Morphologic criteria useful in assessing of lamina propria invasion include the presence of desmoplastic stromal response. and paradoxical differentiation (invasive nests of cells with abundant eosinophilic cytoplasm at the advancing edge of infiltration {2117}). Intraepithelial neoplasia including carcinoma in situ is common in the adjacent urothelium {1547. When small cell differentiation is present. Infiltrating urothelial carcinoma with squamous differentiation Squamous differentiation. Foci of squamous and glandular differentiation are common. B Immunohistochemistry with anticytokeratin may aid in establishing early tumour invasion. 1548.

Glandular differentiation is defined as the presence of true glandular spaces within the tumour. because of its association with high grade tumours {336}. Infiltrating urothelial carcinoma with glandular differentiation Glandular differentiation is less common than squamous differentiation and may be present in about 6% of urothelial car- cinomas of the bladder {1554}.feature in such patients undergoing radical cystectomy. 2. possibly. 2. Pseudoglandular spaces caused by necrosis or artefact should not be considered evidence of glandular differentiation. The diagnosis of adenocarcinoma is reserved for pure tumours {2177}. B Islands of high grade urothelial carcinoma extending through the muscularis propria (detrusor muscle). Squamous differentiation was predictive of a poor response to radiation therapy and possibly also to systemic chemotherapy {336. A Invasive urothelial carcinoma grade 3.07 A.B Infiltrative urothelial carcinoma.2276}. These may be tubular or enteric glands with mucin secretion. A B Fig.B Infiltrative urothelial carcinoma. Cytoplasmic mucin containing cells are present in 14-63% of typical urothelial carcinoma and are not considered to represent glandular differentiation {633}. 98 Tumours of the urinary system . A B Fig. Early invasion not reaching muscularis mucosae (pT1a). The expression of MUC5ACapomucin may be useful as immunohistochemical marker of glandular differentiation in urothelial tumours {1408}. A B Fig. 2.09 Infiltrative urothelial carcinoma.08 A. The infiltration of lamina propria goes beyond the muscularis mucosae (pT1b). A tumour with mixed glandular and urothelial differentiation is classified as urothelial carcinoma with glandular differentiation {923} and an estimate of the percentage of glandular component should be provided.1637. A colloidmucinous pattern characterized by nests of cells "floating" in extracellular mucin occasionally with signet ring cells may be present {1554}.

its infiltrative nature.11 A. Nested variant. The differential diagnosis of the nested variant of urothelial carcinoma includes prominent Brunn nests.1848}. Some nests have small tubular lumens {2562. The differential diagnosis therefore includes urothelial carcinoma with gland like lumina.1109.2562.The clinical significance of glandular differentiation and mucin positivity in urothelial carcinoma remains uncertain {1528}. flattened or urothelial and may show the differentiation towards mucinous cells. There is a marked male predominance {639}. The cyst lining may be absent. paraganglionic tissue and paraganglioma {639. B A Fig. and 70% of patients died 4-40 months after diagnosis.1848. Urothelial carcinoma A Fig.B Nested cell variant of urothelial carcinoma of the urinary bladder. carcinoid tumour. and the nuclear atypia.1109. Nested variant The nested variant of urothelial carcinoma is an aggressive neoplasm with less than 50 reported cases {639. The cysts are round to oval. Closely packed and irregularly distributed small tumour cells favour carcinoma. The pattern should be separated from the nested variant of urothelial carcinoma with tubular differentiation. as well as benign processes like cystitis cystica. cystitis cystica and glandularis. sometimes elongated and may contain necrotic material or pale pink secretions. 2. 2. inverted papilloma.2896}. but invariably the tumour contains foci of unequivocal anaplastic cells exhibiting enlarged nucleoli and coarse nuclear chromatin {639. Nuclei generally show little or no atypia. which is occasionally present is also of value. This feature is most apparent in deeper aspects of the tumour {1848}. 2896}. B Infiltrative urothelial carcinoma. Useful features in recognizing this lesion as malignant are the tendency for increasing cellular anaplasia in the deeper aspects of the lesion. B Infiltrating urothelial carcinoma 99 . The nested variant of carcinoma may mimic paraganglioma. Inverted papilloma lacks a nested architecture.1848. cystitis glandularis or even nephrogenic adenoma. 2562. in spite of therapy {1109}. nephrogenic metaplasia. This rare pattern of urothelial carcinoma was first described as a tumour with a "deceptively benign" appearance that closely resembles Brunn nests infiltrating the lamina propria. Nephrogenic metaplasia typically has a mixed pattern.2896}. including tubular.10 A. Microcystic variant Occasionally urothelial carcinomas show a striking cystic pattern with cysts ranging from microscopic up to 1-2 mm in diameter. is not usually present in nested carcinoma. papillary. and the frequent presence of muscle invasion. and other components. The presence of deep invasion is most useful in distinguishing carcinoma from benign proliferations. which surrounds individual nests. but the prominent vascular network of paraganglioma. and only rarely has deep muscle invasion {639}.

high stage variant of urothelial Lymphoepithelioma-like carcinoma Carcinoma that histologically resembles lymphoepithelioma of the nasopharynx has recently been described in the urinary bladder. The tumours are invariably muscle invasive and this histology is often retained in the histology of metastases. Awareness of the micropapillary histology is important when dealing with metastases of unknown primary. 2. eosinophilic or clear.1228. A. Other markers including CA-125 antigen. B. The micropapillary pattern exhibits two distinct morphologic features. Although the nuclear grade is frequently high. Also. A B C Fig. Micropapillary carcinoma is a high grade.1941. C CK 7 expression.13 A.12 Infiltrative urothelial carcinoma. the invasive portion is characterized by tiny nests of cells or slender papillae. and approximately 60 cases were reported in the literature {81. BerEp4. cytokeratin (CK) 7.A B Fig. B Urothelial carcinoma of the bladder. micropapillary growth pattern is almost always associated with conventional urothelial carcinoma or rarely with adenocarcinoma.3. In contrast. a few micropapillary carcinomas may appear deceptively low grade {81}. often with a central vascular core. 2. Slender-delicate fine papillary and filiform processes. These tumours are more common in men than in women (10:3. or tubular structures containing cellular debris and/or mucin (H&E).1480. Micropapillary variant Micropapillary bladder carcinoma is a distinct variant of urothelial carcinoma that resembles papillary serous carcinoma of the ovary. 100 Tumours of the urinary system .1558. CEA was positive in 13 of 20 cases {1228}. ratio) and occur in late adulthood (range: 52-81 years. and Leu M1.2891}. Papillary tumours. Immunohistochemical studies in one large series disclosed immunoreactivity of the micropapillary carcinoma in 20 of 20 cases for EMA. The individual cells of micropapillary carcinoma show nuclei with prominent nucleoli and irregular distribution of the chromatin.1622. microcystic variant characterized by the formation of microcysts. with microcystic pattern is unrelated to primary adenocarcinoma of the urinary bladder {656. The most common presenting symptom is hematuria. the cytoplasm is abundant. CK 20. in most cases vascular/lymphatic invasion is present. and mitotic figures range from few to numerous. However. with fewer than 40 cases reported {1106. which are contained within tissue retraction spaces that simulate lymphatic spaces. are observed on the surface of the tumours: on cross sections they exhibit a glomeruloid appearance. Most patients present with hematuria and are stage T2-T3 at diagnosis {1106. The presence of a micropapillary surface component or lamina propria invasive tumour without muscularis propria in the specimen should prompt suggestion for rebiopsy because of the high association of muscularis propria invasion. There is a male predominance and patients age range from fifth to the ninth decade with a mean age of 66 years. placental alkaline phosphatase immunoreacted in less than one third of the cases {1228}. mean 69 years). macrocysts. C Micropapillary urothelial carcinoma.2876}.1553}. Histologically. B72. cancer with high incidence of metastases and morbidity. Urothelial carcinoma with micropapillary component must be considered as a primary especially in males and women with normal gynecologic examination {81. Psammoma bodies are infrequent.1228}. Image analysis shows aneuploidy.

2949}. and lymphoma {1553}. This tumour. The presence of recognizable urothelial or squamous cell carcinoma does not exclude lymphoepithelioma-like carcinoma. three who died of their disease and two who died of other causes {1106}. A Characteristic syncytial appearance of neoplastic cells (H&E). The cytoplasmic borders are poorly defined imparting a syncytial appearance.1553}. Almost all of the reported cases have had a component of high grade urothelial carcinoma in addition to the single malignant cells. and occasional neutrophils or eosinophils. The tumour is solitary and usually involves the dome. thus far has been found to be responsive to chemotherapy when it is encountered in its pure form {82. Lymphoepithelioma-like carcinoma may be pure.1106. the diagnosis is based on finding areas typical of lymphoepithelioma-like carcinoma reminiscent of that in the nasopharynx. Carcinoma in situ elsewhere in the bladder is rarely present. posterior wall.1553}.14 Lymphoepithelioma-like carcinoma of the urinary bladder. The histologic features of the lymphomalike and plasmacytoid variants of urothelial carcinoma are characterized by the presence of single malignant cells in a loose or myxoid stroma. and cords of undifferentiated cells with large pleomorphic nuclei and prominent nucleoli. and they are rarely positive for CK20 {1106. especially in cases in which it constitutes the predominant or Infiltrating urothelial carcinoma 101 . it is possible to overlook the malignant cells in the background of inflamed bladder wall and misdiagnose the condition as florid chronic cystitis {1553}. but the presence of a syncytial pattern of large malignant cells with a dense polymorphous lymphoid background is an important clue {1553}.973. often with a sessile growth pattern. The etiopathogenesis of this tumour is unknown. The background consists of a prominent lymphoid stroma that includes T and B lymphocytes. but when lymphoepithelioma-like carcinoma is focally present in an otherwise typical urothelial carcinoma.1553}. the latter being prominent in rare cases. rather. sheets. partial or complete cystectomy. The tumour cells have clear or eosinophilic cytoplasm and eccentrically placed.623}. plasma cells. In some cases. Hybridization with Epstein-Barr virus encoded RNA has been reported to be consistently negative in different series {82. Some examples of lymphoepithelioma-like carcinoma have been described in the ureter and the renal pelvis {820. The epithelial cells of this tumour stain with several cytokeratin (CK) markers as follows: AE1/AE3. Experience at one institution has shown a complete response to chemotherapy and transurethral resection of the bladder {82. CK 7. Another series of nine patients treated with a combination of transurethral resection. predominant or focally admixed with typical urothelial carcinoma. the tumour is composed of nests.1553}. Lymphoma-like and plasmacytoid variants The lymphoma-like and plasmacytoid variants of urothelial carcinoma are those in which the malignant cells resemble those of malignant lymphoma or plasmacytoma {1618. Most reported cases of the urinary bladder had a relatively favourable prognosis A B Fig. The proportion of lymphoepithelioma-like carcinoma histology should be provided in tumours with mixed histology.2571. or in some cases with squamous cell carcinoma or adenocarcinoma {1106.2224}. CK 7 and (in some cases) CK 20 {2571}. histiocytes. although it is suspected that it originates from modified urothelial cells. 2.1553}. poorly differentiated squamous cell carcinoma. The major differential diagnostic considerations are poorly differentiated urothelial carcinoma with lymphoid stroma. and radiotherapy disclosed four patients without evidence of disease. Differentiation from lymphoma may be difficult. The tumour cells stain with cytokeratin (CK) cocktail.623}. Immunohistochemical stains for lymphoid markers have consistently been reported as negative. In some of the cases. CK8. Each of these variants of urothelial carcinoma may cause a significant differential diagnostic dilemma. when pure or predominant.2272. the single-cell component was predominant on the initial biopsy. B Note the characteristic immunostaining with CK. enlarged hyperchromatic nuclei with small nucleoli. these patients behave like patients with conventional urothelial carcinoma alone of the same grade and stage {1106. Histologically. or trigone. Less than 10 cases have been reported.2933. that are possibly derived from basal (stem) cells {1106}. leading to the differential diagnosis of lymphoma/plasmacytoma.

A B Fig. leiomyosarcoma. rhabdomyosarcoma.1555}. D Immunohistochemical expression of smooth muscle actin of the sarcomatoid carcinoma shown in panel B.15 A Infiltrating urothelial carcinoma of the bladder. Rare examples of carcinosarcoma and sarcomatoid carcinomas have been described in the ureter and the renal pelvis {1549}.1960. plasmocytoid variant. liposarcoma angiosarcoma or multiple types of heterologous differentiation may be present {957.16 A Infiltrative urothelial carcinoma. Sarcomatoid variant (with/without heterologous elements) The term sarcomatoid variant of urothelial carcinoma should be used for all biphasic malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of epithelial and mesenchymal differentiation (with the presence or absence of heterologous elements acknowledged in the diagnosis). 1555. epithelial elements react with cytokeratins. glandular or small cell component showing variable degrees of differentiation {1555}. Microscopically.1550}. In some cases the giant cell reaction is so extensive that it may mimic giant cell tumour of the bone {2948}.1238. There is considerable confusion and disagreement in the literature regarding nomenclature and histogenesis of these tumours. Of 6 cases reported by Tamboli et al. 2. strongly argue for a monoclonal origin of both components {957}. 50-77 years old) and most patients present with hematuria {1555. Recent molecular studies. both carcinosarcoma and sarcomatoid carcinoma are included as "sarcomatoid carcinoma" {2175}.2175}. The gross appearance is characteristically "sarcoma-like". 2. 2175} and 70% of patients died of cancer at 1 to 48 months (mean 17 months) {1555} Urothelial carcinoma with giant cells High grade urothelial carcinoma may contain epithelial tumour giant cells or the tumour may appear undifferentiated resembling giant cell carcinoma of the lung. This variant is very infrequent.1555. By immunohistochemistry. The cytological atypia of sarcomatoid carcinoma excludes non-neoplastic lesions such as the postoperative spindle cell nodule and inflammatory pseudotumour {1161. In others they are regarded as separate entities. whereas stromal elements react with vimentin or specific markers corresponding to the mesenchymal differentiation. dull grey with infiltrative margins. benign-appearing bone or cartilage in the stroma or those showing other pseudosarcomatous stromal reactions. It must be distinguished from occasional cases showing giant cells (osteoclastic or foreign body type) in the stroma or urothelial carcinoma showing trophoblastic differentiation. Sarcomatoid carcinoma should be distinguished from the rare carcinoma with metaplastic. The mesenchymal component most frequently observed is an undifferentiated high grade spindle cell neoplasm. B Plasmacytoid variant of urothelial carcinoma of the urinary bladder. Sarcomatoid variant with heterologous smooth muscle elements. Limited information is available about the outcome of patients with these variants of urothelial carcinoma. Sarcomatoid variant without heterologous elements showing spindle cell morphology. exclusive component in a small biopsy sample. The sarcomatoid phenotype retains the epithelial nature of the cells by immunohistochemistry or electronmi- croscopy {1549. one died post-operatively and one is alive without evidence of disease. sarcomatoid carcinoma is composed of urothelial. In some series. A previous history of carcinoma treated by radiation or the exposition to cyclophosphamide therapy is common {1551}. B Infiltrating urothelial carcinoma of the bladder. C Immunohistochemical expression of cytokeratin AE1/AE3 in a case of sarcomatoid carcinoma of the urinary bladder (same case as in panel A). Nodal and distant organ metastases at diagnosis are common {957. The importance of recognizing these variants lies in not mistaking them as a lymphoma or plasmacytoma. The mean age is 66 years (range. {2571} 4 died of their disease. A small subset of sarcomatoid carcinoma may have a prominent myxoid stroma {1238}. 102 Tumours of the urinary system .2175}. The tumours are often polypoid with large intraluminal masses.1549. The most common heterologous element is osteosarcoma followed by chondrosarcoma. A B C D Fig.

in families with hereditary nonpolyposis colon cancer {2411. The pattern may be seen in typical papillary or in situ lesions. and those with neuroendocrine features should be recognized as a specific tumour variant {2816}. Sarcomatoid variant with heterologous elements of osteosarcoma and myxoid sarcoma. but not bladder cancers. High grade invasive urothelial carcinomas may express ectopic human chorionic gonadotropin (HCG) and other placental glycoproteins at the immunohistochemical level only or may contain numerous syncytiotrophoblastic giant cells {365.1553}.20)(p15.656. Very rarely. but is relatively more common in poorly differentiated urothelial carcinomas. No chro- A B C D Fig.1669}. Sarcomatoid variant with heterologous elements of chondrosarcoma showing binucleation and atypical chondrocytes within lacunae. choriocarcinomatous differentiation has been reported. they are extremely rare. D Infiltrating urothelial carcinoma of the bladder. 2.Lipid-cell variant Very infrequently urothelial carcinomas contain abundant lipid in which lipid distended cells mimic signet ring cell adenocarcinoma {1798}. The differential diagnosis is typical liposarcoma and signet ring cell carcinoma. 2.925. Large cell undifferentiated carcinoma as in the lung is rare in the urinary tract. Earlier the literature has included small cell carcinoma. 1954}. and lymphoepithelioma-like carcinoma in this category. There is strong evidence for an increased risk of ureteral and renal pelvic urothelial carcinomas. but these tumours are now recognized as specific tumour variants {656.18 A Urothelial carcinoma. However numerous reports have described families with multiple cases {1313. Urothelial carcinoma with trophoblastic differentiation Trophoblastic differentiation in urothelial carcinoma occurs at different levels. In addition several epidemiological studies showed that urothelial carcinomas have a familial component with a 1. Undifferentiated carcinoma This category contains tumours that cannot be otherwise classified.17 A. B Giant cells in Infiltrating urothelial carcinoma of the bladder. In our experience. B Infiltrating urothelial carcinoma of the bladder. Genetic susceptibility Urothelial carcinoma is not considered to be a familial disease.2891}.1387}. The only constitutional genetic aberration demonstrated so far in a family with urothelial carcinomas in two generation was a t(5. A B Infiltrating urothelial carcinoma 103 Fig. giant cell carcinoma. high grade with giant cells of osteoclastic type. The clear cell pattern may be focal or extensive and awarness of this pattern is important in differential diagnosis with clear cell adenocarcinoma of the urinary bladder and metastatic carcinoma from the kidney and prostate.q11) balanced translocation {2336}.2789}. 1312. Clear cell variant The clear cell variant of urothelial carcinoma is defined by a clear cell pattern with glycogen-rich cytoplasm {1365. C.905. .5 to 2-fold increased risk among first-degree relatives of patients {23.

20 Infiltrative urothelial carcinoma. the data highlight losses of 2q. A small increase in bladder cancer risk was demonstrated for polymorphic variants of several detoxifying enzymes. Chromosomal abnormalities Invasively growing urothelial bladder cancer is characterized by presence of a high number of genetic alterations involving multiple different chromosomal regions. 9p. Non-Invasive Low Grade Papillary Urothelial Carcinoma). 5q. B Trophoblastic differentiation of urothelial cell carcinoma. 5p. C Urothelial carcinoma. D Urothelial carcinoma.19 A Infiltrative urothelial carcinoma. lipoid cell variant with immunohistochemical expression of cytokeratin 7 in most proliferating cells. Somatic genetics The genetic studies to date have used tumours classified according to WHO Tumours Classification (1973) and further studies are underway to link available genetic information to the current classification. Urothelial carcinoma with trophoblastic differentiation. and 17q as most consistent cytogenetic changes in these tumours. The most frequently observed gains and losses of chromosomal regions are separately summarized for cytogenetic.2418. Taken together. 10q. like NAT2 and GSTM1 {700.2189. 8q. The large size of most aberrations detected by CGH or cytogenetics makes 104 Tumours of the urinary system . lipoid cell variant with immunohistochemical expression of epithelial membrane antigen. On the genetic level invasively growing urothelial cancer (stage pT1-4) is highly different from low grade non-invasive papillary tumours (Papillary Urothelial Neoplasm of Low Malignant Potential. B Clear cell variant of urothelial carcinoma of the urinary bladder. 2. 18q and the Y chromosome as well as gains of 1q. CGH. 9q. mosomal alterations were found in 30 additional families with at least 2 affected individuals {22}.1624}. A Clear cell variant of urothelial carcinoma of the urinary bladder.A B C Fig. A. 2191. 8p. patients with sporadic urothelial carcinomas revealed a higher mutagen sensitivity than controls whereas patients with hereditary bladder cancer demonstrated no increased mutagen sensitivity {21}. and LOH (loss of heterozygosity). 2. lipoid cell variant showing the characteristic lipoblast-like features of proliferating cells (H&E). A B Fig. B Urothelial carcinoma. Syncytiotrophoblastic malignant cells with high grade urothelial cancer. A B C D Fig.2419}. Interestingly. It is assumed that invasive urothelial cancers are mostly derived from either non-invasive high grade papillary urothelial carcinoma (pTaG3) or urothelial carcinoma in situ.21 Infiltrative urothelial carcinoma. 11p. C Infiltrative urothelial carcinoma. 2. Urothelial carcinoma with trophoblastic differentiation. HCG immunostaining. Studies using comparative genomic hybridization (CGH) have described an average of 7-10 alterations in invasive bladder cancer {2188.

but it occurs in only 4-6% of invasively growing bladder cancers {983. Table 2.2030.263 9.2709.2844}.2309}.1510.914. Chromosomal location Frequency of alteration by CGH 2 LOH Karyo-typing 1 1p1q+ 2p+ 2q3p3q+ 4p4q5p+ 5q6p+ 6q7p+ 8p8q+ 9p9q10p+ 10q11p11q12p+ 12q+ 13q17p17q+ 18% 11% 2% 13% 4% 7% 7% 4% 20% 9% 7% 18% 13% 16% 11% 22% 27% 4% 11% 11% 9% 4% 9% 18% 2% 4% 4% 7% 11% n.1708. Simultaneous overexpression of two or more adjacent genes may provide cells with a significant growth advantage. EGFR is a transmembrane tyrosine kinase acting as a receptor for several ligands including epidermal growth factor (EGF) and transforming growth factor alpha. without clear cut associations to tumour stage or grade {395.1509. n. MDM2 amplification is frequent in human sarcomas {1270}. In contrast to breast cancer.148.983. 2068. Conversely. MDM2 amplification was unrelated to patient prognosis in one study {2422}. 2390}.2762}.1731.1527. codes for more than 40 different splice variants.a. are important promoters of the cell cycle.1339.2371. but there is disagreement about associations to tumour stage and grade between the studies {1172. In normal cells this autoregulatory feedback loop regulates TP53 activity and MDM2 expression. Importantly.216.1890.533.2762}. = not analyzed. 772. 2152.1495.1991.914. 2540. where HER2 overexpression is almost always due to gene amplification.489. only two of which interact with TP53 and thereby inhibit its ability to activate transcription {173}.132. 2 Only large studies on invasive tumours (pT1-pT4. >50 analyzed tumours) included.2308}.1206. Its activation occurs through interaction with other members of the EGFR gene family.869. making MDM2 overexpression an alternate mechanism for TP53 inactivation. personal communication). MDM2 also promotes TP53 protein degradation. EGFR is amplified in 3-5% and overexpressed in 30-50% of invasively growing bladder cancers {217. Detectable MDM2 protein expression has been reported in 10-40% of bladder cancers. located at 12q14. TOP2A is the target of anthracyclines. but these data were not confirmed by others {1517. H-ras mutations are almost always confined to specific alterations within the codons 12.2394}.2710}.02 Cytogenetic changes in pT1-4 urothelial carcinoma of the urinary bladder.2067. 39-45% 9-72% 17-30% 15-32% 32-57% 18q20q+ Y ________ 36-51% 1 Average frequency from 45 bladder cancers from references {131. HER2 is amplified in 10-20% and overexpressed in 10-50% of invasively growing bladder cancers {225. Tumour suppressor genes Genes that provide a growth advantage to affected cells in case of reduced Infiltrating urothelial carcinoma 105 . About 10-20% of bladder cancers show gene amplification {322. Thus. For example. 457.1368. Simon.1341. and HER2 amplification at 17q23 includes TOP2A in 15%.2289.2394. 1358. H-ras is the only member of the ras gene family with known importance in urinary bladder cancer {279. the anatomy of the 17q23 amplicon may also influence the response to cytotoxic therapy regimens. 6-50% 27% 18-83% 33-82% 43-90% Cyclin dependent kinases (CDKs) and their regulatory subunits. 37-54% 8-30% 17-30% 2-9% 7-24% 8-21% 10-30% 24-25% 16-30% 16-24% 19% 20-23% 29% 37-54% 31-47% 23-47% 13-19% 18-28% 24-43% 22-34% 4-30% 14-30% 19-29% 19-24% 29-49% 13-30% 22-28% 15-37% 20% The epidermal growth factor receptor (EGFR) is another member of the class II receptor family. Depending on the method of detection. and overexpression has been reported in 30-50% of tumours {1464. EGFR also serves as a therapeutic target for several drugs including small inhibitory molecules and antibodies.it difficult to identify genes leading to a selective growth advantage.a.1974.2305. and 61 {1484}.2114. co-amplification and simultaneous overexpression of multiple adjacent oncogenes is often seen. The MDM2 gene.868.2422}. The most important genes for bladder cancer development and progression remain to be discovered.2330.2371. 58% 23% 22% 26% Oncogenes Her2/neu is a transmembrane receptor tyrosine kinase without a known ligand. MDM2 amplification at 12q15 is accompanied by CDK4 amplification in 11% {2422}. the cyclins. the majority of HER2 positive bladder cancers are not amplified. 13.2441. Amplifications or deletions of the adjacent topoisomerase 2 alpha (TOP2A) are present in about 23% of HER2 amplified cases {2417}.3q15. amplification of CCND1 at 11q13 can be accompanied by amplification of FGF4/FGF3 in 88% (R.836. H-ras mutations have been reported in up to 45% of bladder cancers.1980}. Some investigators found associations between CCND1 expression and tumour recurrence and progression or patient survival {1984.1397}. The reason for Her2 overexpression is unknown in these tumours. HER2 has regained considerable interest as the protein is the molecular target of trastuzumab (Herceptin®) therapy in breast cancer. This makes bladder cancer the tumour entity with the highest frequency of HER2 overexpression. the transcription of MDM2 is induced by wild type TP53. The cyclin D1 gene (CCND1) located at 11q13 is one of the most frequently amplified and overexpressed oncogenes in bladder cancer.

2.Fig. and neovascularization {1089}. Although there are no specific mutational hotspots. An online query of the International Agency for Research on Cancer (IARC) database (R7 version. Its gene product regulates the expression of multiple different genes {2757}.23 Infiltrative urothelial carcinoma. september 2002) at www. Fig.25 Infiltrative urothelial carcinoma. mostly located in the central. expression or inactivation are summarized below. Often TP53 mutations can be detected immunohistochemically 106 Tumours of the urinary system . FISH analysis shows two copies if centromere 17 (red) and more than 30 copies of the HER2 gene (green) reflecting HER2 gene amplification. 2. FISH analysis of a human metaphase chromosome spread showing locus specific hybridization signals for the telomeric (green signals) and the centromeric (red signals) regions of chromosome 1. DNA binding portion of the gene. located at 17q23 encodes a 53kDa protein which plays a role in several cellular processes including cell cycle. Thick arrows indicate the most frequent pathways.6-Diamidino-2-phenylindol (DAPI). The chromosomes have been counterstained with 4. The TP53 gene.2619} of invasive bladder cancers (in studies investigating at least 30 tumours). more than 90% of mutations have been found in exons 4-9.iarc. response to DNA damage.24 Invasive urothelial cancer. dotted lines the most rare events. Contribution of several oncogenes in cellular signalling pathways.fr/P53/ {1957} revealed TP53 mutations in 40-60% {1569. Fig. 2. cell death. The typical genetic alterations in genetically stable and unstable tumours are described in the text.22 Putative model of bladder cancer development and progression based on genetic findings. 2. Fig. Mutations of the TP53 gene. are a hallmark of invasively growing bladder cancers.

RB1 which is localized at 13q14.27 Infiltrative urothelial carcinoma. in turn. mutations were detected in 0%. The genes encoding p16 (CDKN2A) and p15 (CDKN2B) map to chromosome 9p21. Progression of the cell cycle depends on the release of pRb from transcription factors including DP1 and E2Fs. the frequency of PTEN mutations is not clear at present. which forms the basis of pT categorization is the most important prognostic factor. As most pT2 and higher stage tumours are high grade. individual prognosis of infiltrating bladder tumours can be poorly predicted based on clinical factors alone.3. Strong nuclear TP53 immunoreactivity in invasive urothelial carcinoma. In efforts to stratify category pT1 tumours further. B Infiltrative urothelial carcinoma. Strong membranous expression of EGFR in a case of invasive urothelial carcinoma.6%. since many TP53 mutations lead to protein stabilization resulting in nuclear TP53 accumulation. deletion or methylation. Immunohistochemical TP53 analysis has practical utility in surgical pathology. The relative high frequency (20-30%) of LOH at 10q23 in muscle invasive bladder cancer {1256} would make PTEN a good tumour suppressor candidate. Tumour multifocality. Histologic grade probably has prognostic importance for pT1 tumours. A metaanalysis of 7 studies revealed that microsatellite instability (MSI) was found only in 12 of 524 (2. and 345 tumour samples. most frequently as a consequence of heterozygous 13q deletions in combination with mutation of the remaining allele {497}. lymph node metastases and presence of systemic dissemination are associated with a poor prognosis. For this purpose.2776}.26 A Invasive urothelial cancer. Cell cycle control may get lost if pRb or inhibitors of cyclin/CDK complexes are inactivated.1530}. Prognostic and predictive factors Clinical factors In general. and 17% of cases {141. 359. Tumour suppressor genes and cell cycle control at the G1/S checkpoint. tumour size of >3 cm.g. or indicate that PTEN is not the (only) target gene at 10q23. plays a crucial role in the regulation of the cell cycle.2112}. by mutation.2845}. and concurrent carcinoma in situ have been identified as risk factors for recurrence and progression {2215}. pRb needs to be phosphorylated by cyclin dependent kinases (CDKs) which are. sub-stag- Fig. alterations of mismatch repair genes (mutator phenotype) are rare. e. In three technically well performed studies including 35. 2. The retinoblastoma (RB1) gene product was the first tumour suppressor gene to be identified in human cancer. A B Fig.2110. Tumour extension beyond the bladder on bimanual examination. In invasive bladder cancer. as well as other specific morphologic features.2%) of cases suggesting that MSI does not significantly contribute to bladder cancer development {1032}. actived by D and E cyclins. a site that is frequently involved in heterozygous and homozygous deletions in urinary bladder cancer of all types. Inactivation of RB1 occurs in 30-80% of muscle invasive bladder cancers {360.1530. Depth of invasion. immunohistochemical TP53 positivity is a strong argument for the presence of genetically instable neoplasia in cases with questionable morphology. stage. infiltration of the ureteral orifice {999}. Some investigators have reported an association between altered Rb expression and reduced patient survival {498. A strong association has been found between RB1 inactivation and muscle invasion {360. 1177. 0. 2. Morphologic factors Morphologic prognostic factors include grade.1172. The PTEN (phosphatase and tensin homology) gene also known as MMAC1 (mutated in multiple advanced cancers) and TEP1 (TGFbeta regulated and epithelial cell enriched phosphatase) is a candidate tumour suppressor gene located at chromosome 10q23.Alterations of 9p21 and p15/p16 belong to the few genetic alterations that are equally frequent or even more frequent in non-invasive low grade neoplasms than in invasively growing/high grade tumours. These results leave the question for the predominant mechanism of inactivation of the second allele open. 63. In addition to a postulated role as a prognostic marker. Infiltrating urothelial carcinoma 107 . However. Alterations of DNA repair genes are important for many cancer types. its value as an independent prognostic marker remains questionable.

TFDP1. GRB2. TAL1 TRK. Carcinoma in situ is more frequent with increasing grade and stage of the associated tumour.2886}. FGF14 HER2. and carcinoma in situ with micro-invasion seems to increase the probability of aggressive behaviour {1547}. GAS6. 60% progression. IL15RA 2% 1-2% 33% CSPG6. It could therefore be expected. micropapillary carcinoma. SKIL Amplification frequency * 2 of 10 3-11% 2% 2% 1-3% 4% 1-2% 1 of 10 1% (C) (C) (K) (K) (C) (F) (C) (C) (C) (C) (C) (C) (K) (K) (C) (C) (C) (F) (K) (C) (C) (F) (S) (C) (F) (C) (C) (C) (C) (C) (F) (S) (C) (F) (S) (C) (C) (C) (F) (S) (P) (C) (C)} TRIO. BIRC5 YES1.ing systems have been proposed on the basis of the level of invasion into the lamina propria. TOP2A. these tumours are highly similar on the genetic level {2188. TAOS1 1% 4-9% 30% 21% 3% 5% 4% 1% 1 of 2 12q13-q21 MDM2. and stage T1 tumours that are high grade {1798} have a recurrence rate of 80%. that similar genetic alterations might be prognostically relevant in all stages. (F) = FISH. CSE1L. CKS1. WNT3 2-24% 3%-7% 4-14% 11% 1 of 14 3% 1-3% 35% 50% 2-9% 2% 1 of 14 2% 17q22-q23 17q24-q25 18p11 FLJ21316. and lymphoepithelioma-like carcinoma may be clinically relevant in patient’s prognosis. CDK4. MUC1. MDS1. PPM1D MAP2K6. An alternative is to stratify patients according to the level of invasion into lamina propria measured by a micrometer attached to the microscope {435. COAS2 RABL2A RAF1 EPHA3 PIK3CA. SKP2 EFNA5 E2F3 EGFR MET. sarcomatoid carcinoma. 20q12-q13 (S) (F) (C) (K) (C) 21p11 22q11-q13 Xp21 Xq21 RPS6KA6 1% 108 Tumours of the urinary system . CECR1. SAS Genetic factors Despite marked differences in the prognosis of pT1 and pT2-4 cancers. STK6. and 35% 10-year survival rate. The pattern of tumour growth has been suggested to be important. HS. Specific subtypes or histologic variants of urothelial carcinomas such as small cell carcinoma. (S) = Southern blotting. FACL5 CCND1. Only studies with more than 20 patients are included.1798}. KSR. EMS1. Stage T1 is frequently found in tumours of high grade. Tumours that infiltrate beyond the muscularis mucosae have a higher progression rate {1039. SKI.03 Amplification sites in invasive bladder cancer. Because vascular invasion is frequently overdiagnosed the prognostic significance of that factor remains uncertain {1436}. If one amplicon was detected only in a single study with less than 20 tumours. ECGF1 Table 2. MYBL2. TFAP2C TPTE MAPK1. Amplicon 1p22-p32 1q21-q24 2q13 3pter-p23 3p11 3q26 5p11-p13 5p15 5q21 6p22 7p12-p11 7q21-q31 7q36 8p12-p11 Putative target gene(s) JUN. Margin status after cystectomy is also an important predictor of prognosis. RPS6KB1.6649. (K) = Karyotyping.2562}. Lymphatic and/or vascular invasion is associated with decreased survival in pT1 tumours (44% 5-year survival). the number of amplified cases is given in relation to the total number of analyzed tumours. WNT2 1-2% 1% 3-6% 2% case report 1% 2% FGFR1 2% 1-3% 2% 4-7% 1-2% 3-8% 33% 1% 4% 8q21-q22 8q24 MYBL1 MYC 9p24 9p21 10p11-p12 10p13-p15 10q22-q23 10q25 11q13 JAK2 MAP3K8 STAM. Capital letters in brackets indicate the method of analysis: (C) = CGH.2419}. NCOA3. a pushing front of invasion had a more favourable prognosis than tentacular invasion in few studies {1226. A multitude of molecular features has been analyzed for a possible prog- 13q3414 16q21-q22 17q11-q21 ARHGEF7. (P) = PCR. nested variant. MC2R BCAS1.

1787. Several investigators reported an association between altered Rb expression and reduced patient survival in muscle invasive cancers {498. Gandour-Edwards et al.2675}.2748}. Thrombospondin (TSP-1) is an inhibitor of angiogenesis that is enhanced by interaction with TP53 protein {961}.1172. However. TP53 Alterations of the TP53 tumour suppressor gene have been by far the most intensively studied potential prognostic marker {2329}.1534.1421.1530. Infiltrating urothelial carcinoma 109 .1876}. there is currently no molecular parameter that is sufficiently validated and has sufficient predictive power to have accepted clinical value in these tumours. A similar result was obtained by Qureshi et al. It is possible that part of these discrepancies are due to different response rates to specific therapy regimens for tumours with and without TP53 alterrations {505.1530} and with tumour progression in pT1 carcinomas {963}. However.2496.2620}. but later studies could not confirm these results {2152.504.2064}. this finding was not confirmed in a subsequent study {1494}. {2495} showed in a series of 242 invasive cancers treated by cystectomy that TP53+/p21. A recent metaanalysis of more than 3700 tumours found a weak but significant association between TP53 positivity and poor prognosis {2329}. In one study with 212 patients. Co-amplification and co-expression of the adjacent topoisomerase 2 alpha (TOP2A) may also play a role for an altered chemosensitivity of HER-2 amplified tumours {1209.1708. EGFR expression was even found to be an independent predictor of progression and survival {1709}. recently described an intriguing link between Her2 expression and improved survival after paclitaxel-based chemotherapy {832}. An independent prognostic role of TP53 alterations was only found in 2 out of 7 trials investigating pT2-4 cancer. A high COX-2 expression was related to good prognosis in a series of 172 patients treated by radical cystectomy {2620}.1359. a reduced TSP-1 expression was significantly associated with disease recurrence and decreased overall survival {960}. In one study.2845}. many subsequent studies could not confirm these data {777.2293}. Angiogenesis The extent of angiogenesis can be quantitated by immunostaining microvessels using antibodies against factor VIII or CD34. and 2) currently used methods for immunohistochemical TP53 analysis are not reliable enough for clinically useful measurement of TP53 alterations. as well as to reduced survival {1717.1510.nostic role in invasively growing bladder cancer {1287. The expression of p27 protein was a striking predictor of prognosis in a set of patients treated by cystectomy and adjuvant chemotherapy {2620}. it appears that 1) TP53 alterations do not sufficiently well discriminate good and poor prognosis groups in properly staged bladder cancers to have clinical utility. 1210}. since more than 50% of these studies found independent prognostic significance.2301} but these associations were not confirmed by others {1509. 1494.tumours were associated with worst prognosis compared to those with TP53+/p21+ phenotype. At least one study has suggested microvessel density as an independent prognostic factor in muscle invasive bladder cancer {260}.2295} and pT2-4 cancers {725}. Cyclooxygenase (COX) is an enzyme that converts arachidonic acid into prostaglandin H2. {2126} in a series of 68 muscle invasive non-metastatic tumours treated with radical radiotherapy. EGFR is overexpressed in 30-50% of invasively growing bladder cancers {217. In another study. most frequently as a consequence of heterozygous 13q deletions in combination with mutation of the remaining allele {497}. it cannot be excluded that a fraction of overstaged TP53 negative pTa tumours with good prognosis has contributed to some of these results {2306}.1890.2475. Early studies suggested a strong prognostic importance of immunohistochemically detectable nuclear TP53 protein accumulation in both pT1 {963.tumours. and TP53 analysis was close to routine application in urinary bladder cancer {1980}. However. however. Some studies suggested that Her2 expression is a predictor for patient survival or metastatic growth {1358.2844}. HER2 overexpression occurs in 30-70% of invasive bladder cancers. TP53 alterations may be clinically more important in pT1 cancer. Despite all this extensive research. COX-2 is one enzyme subtype that is induced by various stimuli including inflammation and occurs at elevated levels in many tumour types.914. Others could not confirm these results {1207. Overall. Early reports linked EGFR expression to an increased risk for tumour recurrence and progression.2305.2095}. Cell cycle regulation p21 and p27 inhibit or stimulate cyclin dependent kinases.457. low COX-2 expression was significantly associated with good prognosis in pT1 cancers {1320}. Stein et al.2611. Inactivation of the retinoblastoma (RB) gene occurs in 30-80% of bladder cancers {360. No survival difference between p27 positive and negative tumours was observed in the same study in patients that had not received adjuvant chemotherapy {2620}.1875. A 60% long term survival was observed in 25 patients with p27+ tumours as compared to 0% of patients with p27.

incorporation of molecular data and identification of biologically aggressive. Sauter F. The current classification reflects work in progress.29 Non-invasive urothelial neoplasm. 3. C Endoscopy. High grade urothelial carcinoma showing atypical urothelial cells that vary in size and shape. If further refinements or modifications to this classification are made. The previously used classifications are not recommended for use. as molecular pathology research progresses. non-invasive papillary Fig. Further. 2. Grignon F. The strong points of the current system are: 1. Lopez-Beltran J. And lastly.J. 110 Tumours of the urinary system . normal urothelium blue. Algaba M. the terms non-invasive have been added to low and high grade papillary carcinoma to emphasize biologic differences between these tumours and infiltrating urothelial cancer. but the diagnostic criteria are further defined for practice. Busch J. Also classifications need to be sufficiently reproducible and comprehensive to be uniformly applied by all pathologists and urologists. Amin C.I. pTa tumour. B Photodynamic diagnostic image of normal bladder and carcinoma in situ.B. Tumour red. normal urothelium blue and carcinoma in situ. 2. Cheville T. classification should reflect genetic differences between tumour categories. As the group of genetically stable tumours appears to include most of the non-invasive low grade carcinomas. The description of the categories has been expanded in the current version of the classification to further improve their recognition. patients having a benign disease should not be threatened by an unnecessary diagnosis of cancer. it is likely that the group that does not deserve the designation of cancer will increase in the future.Non-invasive urothelial tumours G. The nuclei are enlarged. Tumour red. Genetic studies are suggesting two major subtypes of urothelial neoplasms which might have a distinctly different clinical course. they must be on the basis of studies that show superior prediction of prognosis as well as a high degree of reproducibility of morphological or molecular criteria for any newly proposed tumour categories. It includes three distinct categories and avoids use of ambiguous grading such as Grade I/II or II/III. with coarsely granular chromatin. The group of non-invasive high grade carcinomas is large enough to contain virtually all of those tumours that have similar biological properties (high level of genetic instability) as invasive urothelial carcinomas. hyperchromasia. It is believed that the consistent use of the current classification will result in the uniform diagnosis of tumours between institutions which will facilitate comparative clinical and pathological studies. Epstein The aim of classification of tumours has always been to define groups with differences in clinical outcomes that are significant enough to be clinically relevant. The potential for this objective to be met also depends on accurate diagnosis and consistent separation of pTa from pT1 tumours in such studies. abnormal nuclear contours and prominent nucleoli. The presently recommended nomenclature is similar to the WHO-ISUP classification of 1998. A B C Fig. One group (PUNLMP) with particularly good prognosis does not carry the label of ‘cancer’.28 Non-invasive urothelial neoplasm. neoplasms. Gasser D. 2. Hofstädter A. (Papanicolaou staining). A. genetically instable.

Amin ty. Definition Dysplasia (low grade intraurothelial neoplasia) has appreciable cytologic and architectural changes felt to be preneoplastic but which fall short of carcinoma in situ (CIS) {79.B.2587}. 2. similar etiopathogenetic factors may apply in dysplasia.30 Non-invasive urothelial neoplasm. and in this setting dysplasia is usually clinically and A B Fig. B Aberrant immunohistochemical expression of cytokeratin 20 in urothelial dysplasia. Flat urothelial hyperplasia consisting of an increase in number of cell layers. Fig. molecular analyses have shown that at least the lesions in bladder cancer patients may be clonally related to the papillary tumours {1930}. Within the spectrum of hyperplasia a papillary architecture may be present.31 A Urothelial dysplasia with loss of polarity.706}. It may be seen in the flat mucosa adjacent to low grade papillary urothelial lesions. the spectrum of atypical changes in the urothelium that fall short of carcinoma in situ are described here together. Urothelial dysplasia Since dysplasia may be mimicked by reactive inflammatory atypia and even by normal urothelium. most of these patients have concomitant papillary tumours {2545. Clinical features In most cases the diagnosis of bladder cancer precedes dysplasia.I.84. Non-invasive urothelial tumours / Urothelial hyperplaisa / Urothelial displasia 111 . Epidemiology Reliable data is unavailable. 2.Urothelial hyperplasia J. Since dysplasia is conceptually thought of as precursor lesion of bladder cancer. as most registries record dysplasia along with CIS or consider bladder cancer as a single enti- M. When seen by itself there is no evidence suggesting that it has any premalignant potential. However. nuclear atypia and increased cellularity. with few or no significant cytological abnormalities (H&E). Epstein Urothelial hyperplasia is defined as markedly thickened mucosa without cytological atypia.

706. The cells may have increased cytoplasmic eosinophilia and the nuclei have irregular nuclear borders. Cells are uniformly enlarged with a single prominent nucleolus and evenly distributed vesicular chromatin. Dysplasia Lesions show variable often appreciable loss of polarity with nuclear rounding and crowding and cytologic atypia that is not severe enough to merit a diagnosis of CIS. erosion or.1031}.84.706}. in most cases.32 Reactive urothelial atypia due to chronic inflammation. depending on the state of distention.424. Histopathology Normal urothelium Normal urothelium is urothelium without cytologic atypia and overall maintenance of polarity. rarely.706}. 423. Prognostic and predictive factors Dysplasia is most relevant in non-invasive papillary neoplasms. It is three to six layers thick. Mitotic activity may be brisk but without atypical forms.1361.424}. mildly altered chromatin distribution. however progressive lesions do not arise from dysplastic regions {79.1851. instrumentation or intravesical therapy is often available in reactive cases. where its presence indicates urothelial instability and a marker for progression or recurrence (true risk remains to be established) {71. This is not meant to be a "waste basket" term but should be used for lesions with atypia that defy categorization but which the observer feels would benefit from clinical follow-up {424. Alterations vary significantly.2947}. inconspicuous nucleoli and rare mitoses. Fig. infection. whose attributes determine outcome {1361. Urothelial atypia of unknown significance Atypia of unknown significance is not a diagnostic entity. Cytokeratin 20 may be of value in its recognition {261.chronically inflamed urothelium and has nuclear changes clearly ascribable to a reactive/regenerative process. De novo dysplasia progresses to bladder neoplasia in 5-19% of cases. Minimal crowding and nuclear overlap without any cytologic abnormality is within the range of normal {79.706}.1849. and is composed of basal cells. Inflammation may be present in the urothelium or lamina propria {79. ulceration.1023}. Macroscopy Lesions may be inapparent or associated with erythema.2947}. 2. Primary (de novo) dysplasia may present with irritative bladder symptoms with or without hematuria {423.1849.1851}.84. Pleomorphism. or mild architectural alteration {706}.424. It is frequently present with invasive cancer. prominent nucleoli throughout the urothelium and upper level mitoses argue for a CIS diagnosis {79. Reactive atypia Reactive atypia occurs in acutely or 112 Tumours of the urinary system .1866. but a descriptive category for cases with inflammation in which the severity of atypia appears out of proportion to the extent of inflammation such that dysplasia cannot be confidently excluded {424. 1846}.1802. cystoscopically silent. intermediate cells and superficial cells.2450}. A clinical history of stones. Somatic genetics Alterations of chromosome 9 and p53 and allelic losses have been demonstrated {534.

Papillomas tend to occur in younger patients. Almost all patients have a single tumour. since in a prospective study of all bladder tumour cases diagnosed during a two year period in Western Sweden no case of urothelial papilloma was idenfied among 713 patients. The lesions are diploid. papilloma may show extensive involvement of the mucosa. the epithelium lacks atypia and superficial (umbrella) cells are often prominent. Urothelial papilloma 113 . The stroma may show oedema and or scattered inflammatory cells.g. Rarely. if present are basal in location and not abnormal. mitoses rare and proliferation rates low as deemed by immunohistochemical assessment of e. The lesions are often small and occasionaly show concomitant inverted growth pattern.1678}. The male-to- Fig. Busch S.e. There has been significant consensus in previous classification systems with regard to the definition and criteria for exophytic urothelial papilloma. Johansson Definition Exophytic urothelial papilloma is composed a delicate fibrovascular core covered by urothelium indistinguishable from that of the normal urothelium.Urothelial papilloma C. This is referred to as diffuse papillomatosis. Localization The posterior or lateral walls close to the ureteric orifices and the urethra are the most common locations.9:1 {432}. Complete transurethral resection is the treatment of choice. Urothelial papilloma. in the superficial (umbrella) cells only {600. The endoscopic appearance is essentially identical to that of PUNLMP or Low Grade Papillary Urothelial Carcinoma. Alteration of p53 is not seen {469}. with occasional branching in some cases. Epidemiology The incidence is low. ICD-O code 8120/0 female ratio is 1. but without fusion. 2. Mitoses are absent to rare and. but it may be more rare. Clinical features Gross or microscopic hematuria is the main symptom.L. Urothelial papillomas rarely recur (around 8%) {432. Ki-67 expression {469}.1024}. Recent studies claim frequent FGFR3 mutations in urothelial papilloma (75%) {2701} with comparable percentage of mutations in PUNLMP (85%) and Low Grade Papillary Urothelial carcinoma (88%).33 Non-invasive urothelial neoplasm. Cytokeratin 20 expression is identical to that in normal urothelium i. and are seen in children. Histopathology The lesion is characterized by discrete papillary fronds. usually 1-4% of bladder tumour materials reported given the above strict definition.

1190. The trigone is the most common location in the urinary bladder {363. Hyperplasia of Brunn nests and chronic urothelial inflammation have been suggested as possible causes. A. but rare lesions have grown to as large as 8 cm {363. B Inverted papilloma. Clinical features Hematuria is the most common symptom. and within the same lesions. The trabecular type is composed of interanastomosing sheets of urothelium sometimes including cystic areas. 114 Tumours of the urinary system . and urethra in order of decreasing frequency. Most are smaller than 3 cm in greatest dimension.Inverted papilloma G. C Most urothelial cells in this example of inverted papilloma are immunohistochemically reactive with antibodies anti-cytokeratin 7.1071. It is important to not extend the diagnosis to other polypoid lesions with predominantly subsurface growth pattern such as florid proliferation of Brunn nests or areas of inverted growth in non-invasive papillary tumours.1409}. The male: female ratio is about 4-5:1. Mitotic figures are rare or absent {363. 2416. Randomly scattered endophytic cords of urothelial cells invaginate extensively from the surface urothelium into the subadjacent lamina propria but not into the muscular bladder wall. Localization More than 70% of the reported cases were located in the bladder but inverted papillomas can also be found in ureter. The base of the lesion is well circumscribed. Histopathology Inverted papilloma has a relatively smooth surface covered by histologically and cytologically normal urothelium. 2. Dysuria and frequency have been recorded but are uncommon {376}.1409.1843}. A trabecular and a glandular subtype of inverted papilloma have been described {1409}. Epidemiology The lesion occurs mostly solitary and comprises less than 1% of urothelial neoplasms {1843}.34 Noninvasive urothelial neoplasm. A B C Fig. Ages of affected patients range from 10 years {2861} to 94 years {1309} with a peak frequency in the 6th and 7th decades. Macroscopy Inverted papillomas appear as smoothsurfaced pedunculated or sessile polypoid lesions.1049. Anastomosing islands and cords of uniform width distribution appear as if a papillary lesion had invaginated into the lamina propria. The relative proportion of the stromal component is mostly minimal but varies from case to case. the central portions of the cords contain urothelial cells and the periphery contains palisades of basal cells.2101}.1071. Sauter Definition Benign urothelial tumour that has an inverted growth pattern with normal to minimal cytologic atypia of the neoplastic cells. The glandular subtype contains urothelium with pseudoglandular or glandular differentiation. Urothelial cells have predominantly benign cytological features but focal minor cytologic atypia is often seen {363.1190. renal pelvis.596. Foci of mostly non-keratinizing squamous metaplasia are often seen in inverted papillomas. In contrast to conventional papillary urothelial neoplasms. Some cases have produced signs of obstruction because of their location in the low bladder neck or the ureter {503}.596. Etiology The etiology of inverted papilloma is unknown. Neuroendocrine differentiation has also been reported {2534}.2494}.1037.

Papillary urothelial neoplasm of low malignant potential. 2.1190. Mitoses are rare and have a basal location. Histopathology The papillae of PUNLMP are discrete. If the patients were tumour free at the first follow-up cystoscopy.6 years +/-13. Rarely. The tumours are predominantly diploid. Inverted papilloma / Papillary urothelial neoplasm of low malginant potential 115 . The nuclei are slightly enlarged compare to normal. 47% of the patients developed local recurrence but none of the 19 PUNLMP patients progressed {2071}.36 Non-invasive urothelial neoplasm. four patients progressed in stage. These architectural and cytological features should be evaluated in well oriented. An initial diagnosis of inverted papilloma should be challenged if progression is observed as many recurring or progressing cases have exophytic papillary structures in their initial biopsy {78}. in a retrospective study of 112 patients with long term follow up. Fig. ICD-O code 8130/1 the ureteric orifices are the preferred sites for these tumours. in general. Papillary urothelial neoplasm of low malignant potential S.447.35 Macroscopic appearance of a non-invasive low grade urothelial carcinoma with delicate papillae obtained at time of transurethral resection. Cystoscopy reveals. slender and non fused and are lined by multilayered urothelium with minimal to absent cytologic atypia.Somatic genetics Ultrastructure. 68% remained tumour free during a follow-up period of at least 5 years {1104. these tumours are benign. Johansson C. The basal layers show palisading and the umbrella celI layer is often preserved.000 individuals per year. Urine cytology is negative in most cases. non tangentional cut areas of the neoplasm. The polarity is preserved and there is an impression of predominant order with absent to minimal variation in architectural and nuclear features. 35% had recurrence but no tumour progressed. Prognosis If the diagnosis of inverted papilloma is strictly confined to the criteria described above.content of inverted papilloma cells have been non-contributory to the diagnosis in the few evaluated cases {68. The male to female ratio is 5:1 and the mean age at diagnosis (+/. a 1-2 cm regular tumour with a appearance reminiscent of "seaweed in the ocean". Busch Definition Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) is a papillary urothelial tumour which resembles the exophytic urothelial papilloma. Localization The lateral and posterior walls close to significantly lower frequency than in noninvasive papillary carcinomas {1610}. In another study.L.standard deviation) is 64. Clinical features Most patients present with gross or microscopic hematuria.1110}. Recurrent lesions have been observed in less than 1% of the reported cases {376} and progression from pure inverted papil- loma to carcinoma is extremely rare. Recurrences occur. Complete transurethral resection is the treatment of choice. 2. but shows increased cellular proliferation exceeding the thickness of normal urothelium. In a series of 95 cases.1406}. Prognosis The prognosis for patients with PUNLMP is excellent. but at a Epidemiology The incidence is three cases per 100. these patients may present with another tumour of higher grade and/or stage. and DNA. antigenic composition. usually years after the initial diagnosis. two to Fig.9 years (range 29-94) {1107}. In contrast. The latter is virtually identical to that of 112 patients treated at the Mayo Clinic {432}. The cell density appears to be increased compare to normal.

The endoscopic appearance is similar to that of PUNLMP. The mean age (+/. Histopathology The tumour is characterized by slender. contour and chromatin distribution. .000 individuals per year.37 Non-invasive urothelial neoplasm. A B Fig. shape and chromatin pattern. A. there may be a false impression of increased cellularity. 2. 2. Non-invasive papillary urothelial carcinoma. It shows an orderly appearance with easily recognizable variations in architectural and cytologic features even at scanning power. loss of polarity and increased mitotic activity. Mitoses are infrequent and may occur at any level but are more frequent basally. papillary stalks which show frequent branching and minimal fusion.39 Non-invasive low grade papillary urothelial cancer. Clinical symptoms Gross or microscopic hematuria is the main symptom.11. Localization The posterior or lateral walls close to the present but inconspicuous.7 (range 28-90 years) {1107}. but there was only a 25% recurrence rate {432}. The male-to-female ratio is 2. In contrast to PUNLMP. +/. If not. The nuclei are uniformly enlarged with mild differences in shape. it is easy to recognize variations in nuclear polarity. FISH analysis shows monosomy of Chromosome 9 (red dot). The papillary fronds should be evaluated where sectioned lengthwise through the core or perpendicular to the long axis of the papillary frond. low grade Definition A neoplasm of urothelium lining papillary fronds which shows an orderly appearance. 2.B Non-invasive low grade urothelial carcinoma. but easily recognizable variations in architecture and cytologic features. A 116 Tumours of the urinary system B Fig.2 years. In 78% of the cases the patients have a single tumour and in 22% there are two or more tumours {1108}. ICD-O code 8130/21 Epidemiology The incidence is five cases per 100.muscle invasive disease.standard deviation) is 69. Nucleoli may be Fig. ureteric orifices is the site of approximately 70% of the cases.B Papillary urothelial neoplasm of low malignant potential (PUNLMP).9:1. size.38 Non-invasive urothelial neoplasm. A.

In spite of the overall orderly appearance. C The nuclei have open chromatin. CD44. The tumours are usually diploid {2071}.E. ICD-O code 8130/23 Clinical symptoms Gross or microscopic hematuria is the main symptom. Non-invasive papillary urothelial carcinoma. recurrence is common and occurs in 48-71% of the patients {69. 1104. In contrast. Fig. Mitotic figures are readily visible away from the basement membrane. Prognosis Progression to invasion and cancer death occurs in less than 5% of cases. Non-invasive papillary urothelial carcinoma. V. 2. 2. The endoscopic appearance varies from papillary to nodular/ solid sessile lesions. irregular nuclear contours and variably prominent nucleoli. high grade.1110}.2678}.41 Non-invasive papillary urothelial carcinoma. A The papillary fronds are partially fused and lined by markedly atypical and pleomorphic urothelial cells. There is total lack of polarization and maturation.40 Flow chart of the differential diagnosis of non-invasive papillary urothelial tumours. some of which have exfoliated. B The architecture is disordered and there is marked nuclear pleomorphism and hyperchromasia. although some may be delicate. there are tumours that show focal high grade areas and in these cases the tumour should be classified as a high grade tumour. It shows a predominant pattern of disorder with easily recognizable variations in archi- A B C Fig. Patients may have single or multiple tumours. p53 and p63 immunostaining is intermediate between that of PUNLMP and non-invasive high grade papillary urothelial carcinoma {600. high grade Definition A neoplasm of urothelium lining papillary fronds which shows a predominant pattern of disorder with moderate-to-marked architectural and cytologic atypia. Expression of cytokeratin 20. high grade 117 . Reuter Histopathology The tumour is characterized by a papillary architecture in which the papillae are frequently fused and branching.

2678}. size.Fig. Due to the likelihood of associated invasion.42 Non-invasive urothelial neoplasm. The nuclei often show pleomorphism with moderate-to-marked variation in size and irregular chromatin distribution. Mitoses are frequent. shape and chromatin pattern. including the surface. p53 and p63 is more frequent than in low grade tumours {600. the highest of which show marked and diffuse nuclear pleomorphism. and occur at any level. The papillary fronds should be evaluated where sectioned lengthwise through the core or perpendicular to the long axis of the papillary frond. these features should be closely looked for. may be atypical. 118 Tumours of the urinary system . Non-invasive high grade urothelial carcinoma. The tumours are usually aneuploid {2071}. tectural and cytologic features even at scanning power. The thickness of the urothelium may vary considerably and often with cell dyscohesion. including that of papillary cores. Nucleoli are prominent. Detection of cytokeratin 20. 2. it is easy to recognize more marked variations in nuclear polarity. In contrast to non-invasive low grade papillary urothelial carcinoma. Pathologists have the option of recording the presence or absence of diffuse anaplasia in a comment. Within this category of these tumours there is a spectrum of atypia.

44 Non-invasive urothelial neoplasm. hyperchromatic. Urothelial carcinoma in situ 119 .1798. and have a coarse or condensed chromatin distribution. ICD-O code 8120/2 Synonym High grade intraurothelial neoplasia. There is loss of cell polarity with irregular nuclear crowding {425.1552.1845. i. Incidence De novo (primary) carcinoma in situ accounts for less than 1-3% of urothelial neoplasms.2315. the symptoms are usually those of the associated carcinoma. the distal ureters are involved. but is seen in 45–65% of invasive urothelial carcinoma. It may be seen at the basal layer only or may overlay benign appearing epithelium.798.1982}.1844. flat. Macroscopy The mucosa may be unremarkable or erythematous and oedematous.1850.1362. The enlarged nuclei are frequently pleomorphic. 2.1547. In 6 60%. urgency or even hematuria.1678.1982}.2679}. 743. Mitoses including atypical ones are common and can extend into the upper cell layers. Individual cells or clones of neoplastic cells may be seen scattered amidst apparently normal urothelial cells and this is referred to as pagetoid spread {425. frequency. Sesterhenn Definition A non-papillary. 2. Site of involvement Urothelial carcinoma in situ is most commonly seen in the urinary bladder.2836}.Urothelial carcinoma in situ I. 1596. Loss of Fig.2187. They may be asymptomatic or symptomatic with dysuria.e.921. lesion in which the surface epithelium contains cells that are cytologically malignant.1547.2319. Clinical features CIS patients are usually in the 5th to 6th decade of life. in up to 40%. It may be seen in the renal pelvis and proximal ureters {744. they may show large nucleoli. A.A.706. The neoplastic change may or may not involve the entire thickness of the epithelial layer and umbrella cells may be present. It is present in 7-15% of papillary neoplasms {744. The cytoplasm is often eosinophilic or amphophilic. Histopathology Urothelial carcinoma in situ shows nuclear anaplasia identical to high grade urothelial carcinoma. involving ducts and acini.43 Carcinoma in situ. In patients with associated urothelial carcinoma. intercellular cohesion may result in a denuded surface ("denuding cystitis") {688} or in residual individual neoplastic A B Fig. Involvement of the prostatic urethra has been reported in 20-67% and in the prostate.1362. Mucosal erosion may be present. B Urothelial carcinoma in situ.

In such cases cytology is very helpful.1918. Cytokeratin 20 is abnormally expressed in CIS {1023}.45 Non-invasive urothelial neoplasms. Amin T.2552.2421. Prognosis Data suggest that de novo (primary) CIS is less likely to progress to invasive disease than secondary CIS {1981. Gene amplifications and TP53 mutations are rare {818.725.2190.2422}. CIS with multiple aneuploid cell lines appears to be at high risk of progression {1918}. often involving the entire chromosome.1530.2641}. A. The degree of cellular atypia may vary from site to site. R. They appear to be genetically unstable and have many different chromosomal 120 Tumours of the urinary system .2060.A. Non-invasive low grade papillary bladder neoplasms (pTa.2066. Invasively growing and high grade neoplasias are markedly different from noninvasive papillary low grade tumours. Abnormal expression of p53 and RB protein may correlate with progression of CIS {498.A Fig.2294. The genetically unstable category contains high grade (including pTa G3 and CIS) and invasively growing carcinomas (stage pT1-4). DNA aneuploidy occurs in less than 50% {2304. Genetics and predictive factors of non-invasive urothelial neoplasias Genetics of urinary bladder cancer development and progression The genetic studies to date have used tumours classified according to the 1973 WHO Tumours Classification. CIS may consist of predominantly small cells referred to as small cell variant or of rather large cells. Ploidy The DNA analysis shows an aneuploid cell population. Losses of chromosome 9. B Immunoprofile Markers.2934}. and mutations of FGFR3 are the most frequent known genetic alterations in these tumours. which are abnormally expressed in invasive and papillary urothelial neoplasm have also been evaluated in CIS {494.2331. studies are underway to link available genetic information to the current classification.2599. Cordon-Cardo P. Extensive lesions associated with marked symptoms have a guarded prognosis. Cairns M.1748. B Urothelial carcinoma in situ. Urinary bladder cancer has earlier been categorized into "superficial" (pTa. 2237. cells attached to the surface referred to as "clinging" CIS. pT1.964}. Simon P.2803}. CIS) and "invasive" (pT2-4) cancer depending on whether or not tumour infiltration extended to the muscular bladder wall {2133}. Sidransky C.B. CIS commonly is multifocal and may be diffuse. The lamina propria usually shows an inflammatory infiltrate. The nuclear matrix protein NMP22 is present in CIS {2484}. G1-2) have only few genomic alterations and are therefore viewed as “genetically stable” {2189.2931}. some degree of oedema and vascular congestion. 2457}. Patients with CIS and concomitant invasive tumours die in 45-65% of cases compared to 7-15% of patients with CIS and concomitant non-invasive papillary tumour {1846}. It can involve several sites in the urinary tract synchronously or metachronously. Jones D. The genetically stable category includes low grade non-invasive papillary tumours (pTa). in some patients several aneuploid cell populations are present in the same lesion {977.2364. Knowles 2418. Gasser M. Von Brunn nests and cystitis cystica may be completely or partially replaced by the cytologically malignant cells. 2.2115.A. The available genetic data now suggest another subdivision of urinary bladder neoplasia. Two genetic subtypes with marked difference in their degree of genetic instability correspond to morphologically defined entities.

the loci of the cell cycle control genes CDKN2A (p16/p14ARF) and CDKN2B (p15) {1291}.2423}. also in absence of dysplasia {1029}. The high number of individual genetic alterations that are much more frequent in high grade or invasive tumours than in pTaG1-G2 neoplasias makes it unlikely that a relevant fraction of invasive cancers derives from non-invasive papillary low grade tumours. Presence or absence of monoclonality may have an impact on the clinical treatment modalities. It has been shown that a panel of 4 FISH probes is sufficient to detect chromosomal alterations in bladder tumours and tumour cells in voided urines {334. 4q.2307. Loss of DBCCR1 expression has been found in 50% of bladder tumours {984}. On 9q. 2492}. there are also reports of polyclonal cancers. 9p. A CGH study showed predominant deletions at 2q. Losses of the Y chromosome represent the next most frequent cytogenetic alteration in low grade tumours {2310.2859}. 5q.1030.2420. which is consistent with their assumed role as precursors of invasive bladder cancer. Multifocal bladder neoplasms Neoplasias of the urothelium are typically not limited to one single tumour. 17p and18q in this study {2241}.2397. DNA aneuploidy is seen in >90% {2304. and differences are most striking between pTa and pT1 tumours {2304}. These observations have given rise to the ‘field defect’ hypothesis suggesting that environmental mutagens may cause fields of genetically altered cells that become the source of polyclonal multifocal tumours {1362}. A high frequency of LOH at different loci was also observed in 31 CIS samples.2552. by FISH or by cytometry) may be a suitable tool for the early detection of bladder cancer and recurrences.2648}. the putative cell cycle regulator DBCCR1 (deleted in bladder cancer chromosome region candidate 1).1291. 9q. 1898}. 2059. often including high level amplifications and p53 mutations {495.1751.1920. 5q-. 14q. The majority (80-90%) of multicentric bladder neoplasias are of monoclonal origin {437. Chromosome 9 loss can also be found in hyperplasia and even in morphologically normal appearing urothelium {1029. of cystectomy specimens have demonstrated areas of abnormal cells adjacent to grossly visible tumours {1164. Predominant alterations were LOH at 3p. Cytogenetically. It appears possible that selection and overgrowth of the most rapidly growing clone from an initially polyclonal neoplasia might lead to pseudoclonality in some cases of multiple bladder cancer. These data suggest a strong similarity between these tumours and invasively growing cancers. 2934}. occuring in about 50% of bladder cancers of all grades and stages {2189. 2419}.for further progression from pT1 to pT2-4 cancers {263. 11p. CIS) {1031.2316}.1362} (cytogenetic).2304. Only few studies have investigated non-invasive high grade precursor lesions (pTaG3.982. Total or partial losses of chromosome 9 is by far the most frequent cytogenetic alteration in these tumours. Alterations in the cellular DNA content occur frequently in bladder cancer {1120. Precursor lesions of either invasive or non-invasive urothelial tumours include hyperplasia since significant chromosomal aberrations can be found in these lesions.985.2934}.2552.2418}. Genetic differences between minimally invasive (pT1) and extensively invasive (pT2-4) carcinomas are only minimal {2188. seems to be a promising candidate tumour suppressor.2241}.2934}. Because homozygous deletions are slightly more frequent for CDKN2A than for CDKN2B it has been postulated that p16/p14ARF might be the primary target of 9p21 deletions {1975}. This suggests that genetic analysis may be superior to histology for diagnosis of early neoplasia {2492}. which might be involved in cell cycle regulation {984. 9q32-q33 and 9q34. cytogenetic and immunohistochemical mapping studies Chromosomal abnormalities Non-invasive papillary low grade neoplasms (pTa. Two of them have been identified at 9p21. mainly in early stage tumours or in premalignant lesions {915.2492}.2468}. they resemble invasively growing tumours and have many different genomic alterations {2241.1564. Combining pT1 cancers and pTa tumours into one group as "superficial bladder cancer" should be rigorously avoided {2188. and presence of barely visible flat accompanying lesions such as hyperplasia or dysplasia are characteristic for these tumours.1101. Aneuploidy is strongly associated to stage and grade. Only few studies have analyzed genetic changes in dysplasia {1031. and 18q as well as Chromosome 9 The similar frequency of chromosome 9 losses in non-invasive papillary low grade tumours and in high grade invasive cancers triggered extensive research to find the suggested one or several tumour suppressor genes on chromosome 9 that appear to play an important role in bladder cancer initiation {361. frequent recurrence.2656.2467.g.2492}. Chromosomal aberrations can also be seen in histologically "normal appearing urothelium" in bladders from cancer patients.1751. They showed. 13q. High grade non-invasive precursor lesions (pTaG3. and FISH analysis revealed deletions of 9q33 in 73% of samples {2476}.1415. that alterations that are typical for CIS can be also be found in some dysplasias suggesting that at least a fraction of them can be considered CIS precursors. The biologic significance of this alteration is unclear since Y losses can also be found in normal urothelium from patients without a bladder cancer history {2310}. 1030.2419}. 8p. However. Aneuploidy detection (e. Multifocality.1492. This is also consistent with the clinical observation that the vast majority of invasive bladder cancer was not preceded by a pTa G1/G2 tumour {1363}.993.733.2059. gains at 5p and 20q in 18 pTaG3 tumours {2934}.2418. and 6q. G1-2) have only few cytogenetic changes suggesting that these tumours are genetically stable neoplasms {2189.aberrations. 10q.2931}.2304}. It is assumed that neoplastic cells that have originated in one area later spread out to other regions either by active migration through the urothelium or through the urine by desquamation and reimplantation {992}.2191.541. CIS) are very different from low grade neoplasias.2405. containing the PTCH. 1488.2 553. Mapping studies using microsatellite analysis identified multiple common regions of loss of heterozygosity (LOH) {361. Another three putative suppressor gene loci have been mapped to 9q13-q31. Some reports have suggested a possible role of 5p+.986. Morphological. 5q. Mutations of DBCCR1 have not been reported yet.2883}. DBCCR1 and TSC1 genes {988}. Although hemizygous deletions have been seen in rare cases it is believed that promoter hypermethylation and homozygous deletions are the main mechanisms Genetics and predictive factors of non-invasive urothelial neoplasias 121 .

These data support the idea that these categories represent variations of one tumour entity (non-invasive low grade papillary tumours. However. Increased expression of Ras protein has been described in CIS and high grade tumours but not in hyperplasia or low grade tumours in an early 9q- 38%(C) 10p+ 10q11p- 5%(C) 28%(C) 17%(C) 54%(L) 11q11q+ 12p+ 12q+ 13q14q17p17q+ 18q20q+ Y 23%(C) 36%(L) 1 of 2 (F) Morphological factors Histologic grade is a powerful prognostic factor for recurrence and progression in non-invasive urothelial tumours {706.2403}. mutations have been linked to a lower risk of recurrence indicating that this genetic event may identify a group of patients with favourable disease course {2700}.04 Overview of cytogenetic changes in non-invasive urothelial of the urinary bladder. they showed comparable frequencies of p53 alterations (50-70%) {1031. 2761}. In one study. These mutations are predicted to cause constitutive activation of the receptor. The role of the sonic hedgehog receptor PTCH and the tuberous sclerosis gene TSC1 in bladder cancer is only poorly investigated to date. Urothelial papilloma has the lowest risk for either recurrence or progression {426. 10 or 15 that have been previously described as germline mutations in skeletal dysplasia syndromes {369.2766}. In the largest study reported to date. As discrimination between non-invasive and invasive tumours is not reliably possible on cystoscopy alone. while PUNLMP has a higher risk for recurrence (up to 35%) and a very low risk for progression in stage {432. (F) = FISH (FISH analyses of ICGNU have been included because of the lack of CGH data in this tumour type).for DBCCR1 silencing {984. Table 2. study {2736}. 1247. the probability of future recurrences. The risk of recurrence decreases with each normal cystoscopy and is less than 10% at 5 years and extremely low at 10 years if all interval cystoscopies had been normal. 74% of pTa tumours had FGFR3 mutation as compared to 16% of T2-4 tumours {243}. 53 of 62 tumours of low malignant potential (85%). multifocal tumours and those with diffuse appearance have a higher risk of recurrence {773}. irritative symptoms and extensive disease are associated with poor prognosis {71}. Short disease-free interval is also an indication for future recurrence.3. Microscopic or gross hematuria are the most common findings {1719}. urgency and frequency occur if the tumour is localized in the trigone. In case of recurrent tumour. In case of carcinoma in situ. In a recent study {2701}. and the retinoblastoma gene (RB) {1749.1104. However.148.867. increase to approximately 80%. All mutations described are missense mutations located in exons 7.1678}.2066}. TP53 and RB Alterations of TP53 {818. 122 Tumours of the urinary system .2761}.868. Few studies have examined gene alterations in CIS or pTaG3 tumours. HER2 & EGFR Overexpression of HER2 or EGFR have been described in a variable fraction of pTaG1/G2 tumours depending on the analytical methodology {914. have only recently been identified as a molecular alteration that is characteristic for pTa tumours.1748.1107.1610}. and loss of p21 (50-70%) {472.2442.869.132. the role of RAS especially in non-invasive bladder cancer needs further clarification {2395}. half of all the tumours will recur at some time. in case of large tumour volume due to reduction of bladder capacity. Prognosis and predictive factors Clinical factors There are no specific urinary symptoms of non-invasive bladder tumours. or in case of carcinoma in situ. Chromosome Frequency of alteration in pTa G1/2 1p1q+ 2p+ 2q3p3q+ 4p4q5p+ 5q6p+ 6q7p+ 8p8q+ 9p4-5%(C) 1%(C) 6%(K) 1%(C) 2-5%(C) 1-10%(C) 2%(C) 3%(K) 4-20%(C) 3%(K) 1-5%(C) 1-10%(C) 16%(K) 5-10%(C) 19%(K) 5-15%(C) 19%(K) 5-10%(C) 3%(K) 36-45%(C) 28%(K) 15-33%(L) 45%(C) 31%(K) 2 of 7 (L) 3%(K) 5%(C) 9%(K) 10%(C) 16%(K) 1 of 3 (L) 6%(C) 3%(K) 5-25%(C) 1%(C) 1-15%(C) 3%(K) 0-20%(C) 19%(L) 1%(C) 9%(L) 1-5%(C) 6%(K) 10-30%(C) 7-10%(C) 3%(K) 7-15%(C) 10-20%(C) 6%(K) 11%(C) 33%(C) 39%(C) 33%(C) 28%(C) 29%(K) 29%(L) 5%(C) 5%(C) 17%(C) 56%(L) 70%(L) 81%(F) 60-64%(L) 3%(K) 13%(C) 17%(C) 5%(C) 39%(C) 5%(C) 5%(C) 22%(C) 17%(C) 28%(C) 33%(C) 11%(C) 33%(C) 5%(C) 28%(C) 22%(C) 45%(C) 40-77%(F) 61-76%(L) 74%(F) 52-61%(L) 1 of 2 (F) 65%(L) 20%(L) 32%(L) 52%(L) 31%(L) pTa G3 CIS 1 of 2 (F) FGF receptor 3 (FGFR3) Mutations of the gene. At the time of first diagnosis approximately 70% of the tumours are non-invasive and of these only 5 to 10% will progress to infiltrating tumours {544}.134.1758}.1119}. comparable FGFR3 mutation frequencies were reported in 9 of 12 papillomas (75%). Irritative bladder symptoms such as dysuria. Patients with papilloma and PUNLMP have essentially a normal agerelated life expectancy. Large tumours.1440. complete transurethral resection of any visible lesion of the bladder including deep muscle layers is usually performed.1460}. HER2 overexpression (50-75%) {489. (L) = LOH. 2112} occur in a fraction of non-invasive papillary low grade tumours that is much smaller than in invasive cancer. Non-invasive low ________ (C) = CGH. 797} or p27 (50%) {797} as described in invasive cancers.2476}.2029. and 15 of 17 low grade papillary carcinomas (88%). located at chromosome 4p16.654.2710. Regular cystoscopic follow-up is recommended at intervals for all patients with non-invasive tumours to detect recurrent tumour at an early stage. genetically stable).2639.1757. or EGFR overexpression (45-75%) {373. (K) = karyotyping/classical cytogenetics (average of 32 cases from references {131.

Genetic factors Hundreds of studies have analyzed the prognostic significance of molecular features in non-invasive urinary bladder cancer {1340. clusterin overexpression {1746}. several studies showed that rapid tumour cell proliferation as measured by flow cytometry. A systematic review of large series of pT1 tumours resulted in a downstaging to stage pTa in 25-34% of tumours {19. 4p. 5q. Only in these cases.2421}. PCNA labeling.1461}.2942}.600. have been suggested as a prognostic marker in pTa tumours {2296}.2065. renal pelvis) are at increased risk for recurrence.726. Tumours frequently progress in stage. 2066. Multicentric neoplastic lesions in the bladder are clonally related in about 80-90% of cases {992}. 6q. and the frequency of most molecular changes is highly different between pTa and pT1 tumours. none of 10 tumours with a normal cytokeratin 20 staining pattern recurred {1024}. molecular changes that decrease genetic stability are expected to herald poor prognosis in these patients. Since the risk of progression is much higher in pT1 than in pTa tumours. Accordingly. mitotic index.2306.2322}. progression or death due to disease {531.2450}. Studies using fluorescence in situ hybridization (FISH) have indeed shown a strong prognostic significance of genetically abnormal cells for early recurrence in cystoscopically and cytologically normal bladders {801.1104. known to decrease genomic stability. the risk of recurrence is determined by the amount and biologic properties of neoplastic cells remaining in the bladder. Indeed.1314.1579. there is no thoroughly evaluated molecular marker that has sufficient predictive power to be of clinical value in these tumours. Early studies suggest that mutations are linked to a decreased risk of recurrence {2700}. 726. Large tumours (>5 cm) are at an increased risk for recurrence and progression {1072}. loss of p63 expression {2678}.2827}. 1107.2633. The prognosis for non-invasive high grade carcinomas is strikingly different. Cytokeratin 20 expression and FGFR mutations are examples of markers that may be representative for a clinically distinct tumour subtype without having a direct role for the development of early recurrence. 2298}. and death due to disease can be as high as 65% {1247. Genetics and predictive factors of non-invasive urothelial neoplasias 123 . because an acquisition of multiple additional molecular changes may be required to transform non-invasive low grade neoplasia to invasive cancer.1179. Cytokeratin 20 is normally expressed in the superficial and upper intermediate urothelial cells. LOH at chromosome 16p13 {2879}.2725.2496. but only up to 12% of patients progress in stage {433. and 18q {2191}. abnormal expression of pRb {963}. CIS is a stronger adverse factor {425. A too large fraction of overstaged "false" pT1 tumours can even suggest independent prognostic impact of molecular features in combined pTa/pT1 studies.grade carcinomas recur frequently (up to 70%). Mutations of the FGF receptor 3 (FGFR3) have recently been identified to occur in more than two thirds of non-invasive low grade urothelial carcinoma {243}. In fact. reduced thrombospondin expression {898}.425. it must be assumed that interobserver variability in the distinction of pTa and pT1 tumours may markedly influence the results {19.1981.1362}.1460}. Patients with multifocal tumours in the bladder or involving other regions of the urothelial tract (ureter. or Ki67 labeling index predicts an increased risk of or recurrence in these tumours {573.2835}.2633. and reduced expression of E-cadherin {1511}. Other molecular features that were proposed to predict tumour recurrence in non-invasive papillary low grade tumours include overexpression of proline-directed protein kinase F {1132}. the molecular characteristics of the removed tumour may be representative of the "entire" disease. p14ARF promoter hypermethylation {632}. loss of E-cadherin expression {1210}.2418. centage of pT1 cancers varies between 20% and 70% in consecutive series of "superficial bladder cancers" {249. In theory. Early tumour recurrence could also be predicted by the analysis of urine cells after surgical removal of all visible tumours. Molecular parameters that were suggested to herald a particularly high risk of progression include p53 accumulation {2294}.2835}.1452. Overall. After complete resection of a tumour.2019}.1981}. Risk of progression Data on the prognostic importance of genetic changes for progression of noninvasive low grade neoplasias are largely missing because of the rarity of progression in these patients. 1518. the per- Risk of recurrence Non-invasive urothelial neoplasia often involves invisible flat neoplastic lesions in addition to a visible papillary tumour {285. The presence of dysplasia and CIS in the nonpapillary urothelium is associated with increased risk for progression in stage and death due to disease {71. p53 alterations. as well as alterations of chromosomes 3p. In a study of 51 non-invasive papillary tumours. The best candidates for predicting early recurrence include molecular changes that are related to an increased tumour cell proliferation or an improved potential for multicentric tumour extension. expression of the imprinted H19 gene {115}. 10q. urethra.1512. 5p. There is circumstantial evidence that in some studies the substantial biological differences between noninvasive (pTa) and invasively growing (pT1) neoplasias were not taken into account {2189.

1791}).3% of bladder tumours in males. Similar findings with respect to black–white differences in proportions of the different histological types of bladder cancer have been reported from clinical series. Tanzania). 94% urothe- lial) {2013}. and in east and south-east Africa (Zimbabwe. B Bladder squamous carcinoma in diverticulum. japonicum) account for the majority of human infections. whites having 94. In some West African countries (Mali. bladder cancer risk Schistosomiasis Schistosomes are trematode worms that live in the bloodstream of humans and animals.Squamous cell carcinoma D.E. ICD-O code 8070/3 Epidemiology The most common histological type of bladder cancer is urothelial carcinoma. These observations (as well as clinical features such as sex ratio. In the United States. Niger). It has been estimated that the relative risk for current smokers is about 5-fold of that in non-smokers {791}. Three species (Schistosoma haematobium. Squamous cell carcinoma (SSC) of the bladder is much less frequent. rather than urothelial carcinomas. respectively. Cystectomy specimen. mansoni and S. The evidence linking infection with Schistosoma haematobium with bladder cancer has been extensively reviewed {419. Malawi.4% in females. There are essentially three lines of evidence: Clinical observations that the two diseases appear to frequently co-exist in the same individual. The risk of bladder cancer in smokers is 2-6 fold that of non-smokers {1158}. as it does in Egypt.846. and that the bladder cancers tend to be of squamous cell origin.2739}. there are marked differences in histology between Blacks (36% SCC. but the effect of occupational exposures has not been quantified for different histological types. as well as with increasing intensity of smoking {313}. Several studies investigated this relationship. Worldwide. comparing infection with S. and 3. the majority of bladder cancers in Algeria and Tunisia (high incidence countries) are urothelial carcinomas. it constitutes about 1. The risk increases with increasing duration of smoking. Schmitz-Dräger R. presence of calcified eggs identified by X-ray or information from a questionnaire {199. In South Africa. taking as a measure of infection the presence of S. which comprises 90-95% of bladder cancers in Western countries {2016}. Descriptive studies showing a correlation between the two diseases in different populations. the differences in histology by race are small. with SCCs comprising less than 5%. The A 124 Tumours of the urinary system B Fig. in Blacks. Case-control studies.1859. The risk increases with the increasing lifetime consumption.46 A Squamous cell carcinoma.3% squamous cell carcinomas (SCCs). haematobium eggs in a urine sample.5% urothelial and 1. as well as with increasing intensity of smoking {1271}. is increased in various occupational groups. haematobium in bladder cancer cases and control subjects.J. Simon J. SCC predominates.687.8% and 3. while the proportions are 87. Occupational exposures As described earlier. In Africa. Tobacco smoking is also an important risk factor for SCC of the bladder. for example in the Durban hospitals {955}. Etiology Tobacco smoking Tobacco smoking is the major established risk factor of bladder cancer. and for those with the highest consumption (more than 40 pack-years) is about 11 {791}.1152. 2. Grignon M. El-Bolkainy B.N. S.2%. 41% urothelial) and Whites (2% SCC. mean age at diagnosis and stage) relate to the prevalence of infection with Schistosoma haematobium. . nodular squamous cell carcinoma associated with leukoplakia.J. with. Tyczynski Definition A malignant neoplasm derived from the urothelium showing histologically pure squamous cell phenotype.

683. 2.12. haematobium-infected patients {14. 2. the tumour should be classified as urothelial carcinoma with squamous differentiation {2276}. Histopathology The diagnosis of squamous cell carcinoma is restricted to pure tumours {232. S. haematobium-infected patients results in higher concentrations of certain metabolites (e. Fig.2242}. Elevated β-glucuronidase levels in schistosome-infected subjects could increase the release of carcinogenic metabolites from their glucuronides. B Urine cytology. Nitrate. . 2157.1091.1090.745.2156. anthranilic acid glu- curonide.g.1093. Some of these metabolites have been reported to be carcinogenic to the urinary bladder {332}. 3-hydroxy-L-kynurenine and acetyl-L-kynurenine) in pooled urine {11. polypoid.A B Fig. although schistosome-infected humans are known to have elevated βglucuronidase activity in urine {9. haematobium egg with terminal spine. including the production of nitric oxide by inflammatory cells (activated macrophages and neutrophils) {2240. often filling the bladder lumen {2297}. Alterered metabolism of mutagens may be responsible for genotoxic effects {851.2158}.15. although some are predominantly flat and irregularly bordered {1884} or ulcerated and infiltrating {1233}. Quantitatively altered tryptophan metabolism in S. Macroscopy Most squamous cell carcinomas are bulky. genotoxic effects and activation of carcinogens through several mechanisms.49 Invasive squamous cell carcinoma associated with calcified Schistosoma haematobium eggs. and micronuclei were more frequent in urothelial cells from chronic schistosomiasis patients than in controls {2239}. The invasive tumours may be well differSquamous cell carcinoma 125 Fig.1091. estimated relative risk varied from 2 to 15 compared with non-infected subjects. Lkynurenine. 1468} and may play an intermediary role in the genesis of squamous-cell carcinoma via a variety of metabolic effects.806}. especially if associated with dysplasia.852. 3-hydroxyanthranilic acid. 2399}. they may be carcinogenic to bladder mucosa. Secondary bacterial infection of Schistosoma-infected bladders is a well documented event {678. Nitrosamines are formed by nitrosation of secondary amines with nitrites by bacterial catalysis (or via urinary phenol catalysis).47 Squamous cell carcinoma.10. spindle cells of squamous carcinoma.48 Low grade squamous cell carcinoma of the bladder with calcifyed schistosomal eggs (H&E). Immunological changes have been suggested as playing a role {854. nitrite and N-nitroso compounds are detected in the urine of S. indican. No data are available at present to confirm this association. 2. for reasons that are unknown. Pathogenesis Numerous explanations have been offered for the proposed association between schistosomiasis and human cancers: Chronic irritation and inflammation with increased cell turnover provide opportunities for mutagenic events. necrotic masses. A Urine cytology.2643}.2642.1449.805. 1092.1916}. The presence of necrotic material and keratin debris on the surface is relatively constant. solid.2297}. Genetic damage in the form of slightly increased sister chromatid exchange and micronucleus frequencies were seen in peripheral blood lymphocytes harvested from schistosomiasis patients {104. If an identifiable urothelial element including urothelial carcinoma in situ is found.853}. supports a diagnosis of squamous cell carcinoma. The presence of keratinizing squamous metaplasia in the adjacent flat epithelium. Squamous metaplasia is identifiable in the adjacent epithelium in 17-60% of cases from Europe and North America {232}. 679.

No significant genetic differences have been found between Schistosoma associated and non Schistosoma associated urothelial carcinoma with or without squamous cell differentiation {225. overall 5-year survival was 56%.230 9}.2) it was 67% and for non organ-confined (pT3. Methylation of DNA as shown by detection of O6-methyldeoxyguanosine has been found in a high percentage of patients with schistosomiasis-associated cancers in Egypt {149.1708. 8p. Tstage. and HER2 expression (10-50%) {225.2141. Circumscribed high level amplifications were reported at 8q24 (2 cases) and 11q13 (one case) in this study.1527.1974. with marked nuclear pleomorphism and only focal evidence of squamous differentiation. 735.2380}. 1708. 4q. 2373}.489. Fig. Only few non Schistosoma associated “sporadic” SQCC have been molecularly analyzed. Somatic genetics Genetic analyses of squamous cell carcinomas (SQCC) of the urinary bladder focused on Schistosoma associated tumours.4) it was only 19% {692}. while deletions were most frequent at 3p. 6p. sex and age are not prognostic in squamous cell bladder cancer {692}. EGFR overexpression (3070%) {337. In contrast.2309} were also found at comparable frequencies in Schistosoma associated SQCC {2141}. Cytogenetic and classic molecular analyses showed overrepresentation of chromosomal material predominantly at 5p. 9p (2/11).489. n=135) {987.1527. while neoadjuvant radiation improves the outcome in locally advance tumours {866}. which is not significantly different from the findings in urothelial cancer. TP53 mutations in Schistosoma associated SQCC included more base transitions at CpG dinucleotiodes than seen in urothelial carcinomas {2784}. There are no uniformly accepted criteria for grading of squamous cell carcinoma. lymph node involvement and tumour grade have been shown to be of independent prognostic value {2118. and 13q (5/11) as well as gains of 1q (3/11). 5q.2784}. and 20q. the rate of p53 positive tumours ranged between 30-90% in all studies (average 40%.50 Well differentiated squamous cell carcinoma of the urinary bladder with extensive keratinization (H&E).1858. 2. 2.914. 13q.1921}.2710} and another eleven by comparative genomic hybridization (CGH) {681}.2127}. Morphologic factors Pathologic stage is the most important prognostic parameter for squamous cell carcinoma {692}.912. and 18q {74. e. and 20q (4/11) {681}.2152.1884}. The predominant changes in the CGH study were losses of 3p (2/11).2118.51 Squamous cell carcinoma. Several studies suggested differences in the frequency and type of p53 alterations between urothelial carcinoma and Schistosoma associated SQCC {987.150}.1509. prominent intercellular bridges. However. Squamous cell carcinoma of the bladder has been graded according to the amount of keratinization and the degree of nuclear pleomorphism {745. Patients undergoing radical surgery appear to have an improved survival as compared to radiation therapy and/or chemotherapy. for those patients with organconfined tumour (pT1. 2.52 Keratinizing squamous metaplasia. 836. Fig. They may also be poorly differentiated. In a series of 154 patients.1573. 2141. 8q (4/11). Four cases of SQCC had been investigated by classical cytogenetics {731. 8q. The tumours are staged using the AJCC/TNM system as for urothelial carcinoma {944}.836. In one study. 17q.Fig.2784}.914. and minimal nuclear pleomorphism.1509. 7p. 17p. entiated with well defined islands of squamous cells with keratinization.1974. 11q. Several studies have demonstrated 126 Tumours of the urinary system . A basaloid pattern has been reported {2682}.2152.g.681. Other molecular alterations known to occur in urothelial carcinomas such as HRAS mutations (6-84%) {2117. Prognosis and predictive factors Clinical criteria Patient-related factors.

2851}. Fig.53 Verrucous squamous cell carcinoma of the urinary bladder showing typical exophytic papillary growth and high degree of differentiation.2772}. verrucous carcinoma has a good prognosis.N. but results Fig. papillary. Tumours developing in patients with longstanding anogenital condyloma acuminata and condyloma acuminatum of the urinary bladder are reported suggesting a possible link to HPV infection {186. El-Bolkainy ICD-O code 8051/3 Verrucous carcinoma is an uncommon variant of squamous cell carcinoma that occurs almost exclusively in patients with schistosomiasis.745. Cases having typical verrucous carcinoma with an infiltrative component are described and should not be included in the verrucous carcinoma category {1603}. the tumour is composed of papillary cores covered by benign squamous epithelium without koilocytic atypia. Cases of classic verrucous carcinoma are associated with minimal risk of progression whether associated with schistosomiasis or without {680. In most cases the cystoscopy shows a solitary papillary lesion {428}. 2772. 2. B.1102.2772. Verrucous squamous cell carcinoma / Squamous cell papilloma 127 .1102.2851}.682}.J. Verrucous squamous cell carcinoma D. Genetic predictive factors Nothing is known on the impact of genetic changes on the prognosis of SQCC of the urinary bladder. proliferative squamous lesion. Helpap Squamous cell papilloma of the urinary bladder is a very rare benign. respectively {692}. pushing. This cancer appears as an exophytic. This has not been a uniform finding however {2263}. in the bladder are limited. 52% and 35%. 5-year survivals for Grade 1. Squamous cell papilloma ICD-O code 8052/0 women without specific clinical symptoms {428}. minimal nuclear and architectural atypia and rounded. One recent study analyzing 154 patients that underwent cystectomy suggested that a higher number of newly formed blood vessels predicts unfavourable disease outcome {692}.691. or "warty" mass with epithelial acanthosis and papillomatosis. It is not associated with human papillomavirus (HPV) infection. Isolated cases of verrucous carcinoma of the urinary bladder have been described in the literature from non-endemic areas {691.54 Verrucous squamous cell carcinoma associated with schistosoma infection. 2. deep borders. Grignon M. 2 and 3 squamous cell carcinoma was 62%.1884}.grading to be a significant morphologic parameter {692.6% of bladder cancers in such a setting {680. It occurs in elderly Histologically. accounting for 3% to 4. In other organs. In one series.

or infiltrating and may exhibit a gelatinous appearance.G.953. Clinical features Adenocarcinoma of the urinary bladder occurs more commonly in males than in females at about 2. Sidransky P. Tamboli M. signet ring cell {257.6:1.1388. The NOS A B Fig.P. this tumour may be exophytic.2832}. hepatoid {344}. Ayala P.2901}. Haematuria is the most common symptom followed by dysuria. the surface shows intestinal metaplastic changes that merge with the invaginating glandular elements. papillary. A B Fig. 128 Tumours of the urinary system .56 A Signet ring cell carcinoma of bladder.952}. clear cell {456. These include: enteric (colonic) type. {953} adenocarcinoma not otherwise specified (NOS) {953}. but mucusuria is rarely seen {953}. B Adenocarcinoma. It includes primary bladder adenocarcinoma and urachal carcinoma. The lamina propria exhibits diffuse infiltration of signet ring cells. Macroscopy Grossly. mucinous (colloid) {953}. pure adenocarcinoma of the bladder may show different patterns of growth {953}. Schoenberg E.1192. 2. colonic type. Simon Definition A malignant neoplasm derived from the urothelium showing histologically pure glandular phenotype. 2.1245. B In this illustration there are multiple glands embedded in a loose stroma.Adenocarcinoma A.N. sessile. Epidemiology Bladder adenocarcinoma is an uncommon malignant tumour accounting for less than 2% of all the malignant urinary bladder tumours {1192. Cairns R. Hepatoid adenocarcinoma of the urinary bladder showing irregular areas of conventional adenocarcinoma (H&E).2612}.878. Oliva D. 1813. ulcerating.1263. Histopathology Histologically. A In this view.55 Adenocarcinoma of bladder. and affects adults with a peak incidence in the sixth decade of life {24. and mixed {953}. El-Bolkainy M.

2521. which has been reported to be of help in distinguishing primary adenocarcinoma of the bladder from metastatic colonic adenocarcinoma {2777}.2538. it is not uncommon to find a mixture of these growth patterns.2538} and cystocele. 2.2521. can have a monocytoid or plasmacytoid phenotype. Fig. such as may be seen in a non-functioning bladder {341. The enteric type closely resembles adenocarcinoma of the colon. Differential diagnosis The differential diagnosis includes metastatic disease or direct extension.5.2791}. and an accompanying in situ component with numerous signet ring cells may be present {456}. type consists of an adenocarcinoma with a non-specific glandular growth.2791}. 2. There is no generally accepted grading system ascribed to adenocarcinoma of the bladder. papillary. a recent study is challenging this theory {499}. staining). and none developed car- Immunoprofile The immunohistochemical profile of these tumours that has been reported in the literature is variable and closely matches that of colonic adenocarcinomas {2572. Secondary involvement is much more common than the primary adenocarcinoma of the bladder.2777}.58 Adenocarcinoma. 2898}. A pure pattern is rarely seen. 2379. cribriform and flat.1504. Villin has recently been reported to be positive in enteric type adenocarcinomas of the urinary bladder {2572}. Fifty-three patients with extrophy of the bladder were followed for more than 10 years.A B Fig. most commonly from colorectum and A B Fig.60 Adenocarcinoma of the urinary bladder with squamous area. Reports of cytokeratin (CK) 7 positivity are variable ranging from 0-82%. A High power view of hepatoid adenocarcinoma showing billiary pigment (H&E).1% {1677. chronic irritation {660. The risk of development of adenocarcinoma in extrophy is in the range of 4. 2.2396. Although traditionally investigators have felt that intestinal metaplasia is a strong risk factor for the development of adenocarcinoma in extrophy {341. but various combinations of these are the rule {405}. Precursor lesions Most cases of adenocarcinoma of the urinary bladder are associated with longstanding intestinal metaplasia of the urothelium. Adenocarcinoma 129 . This is not considered to be glandular differentiation (H&E).1928. Tumours that show abundant mucin with tumour cells floating within the mucin are classified as mucinous or colloid type. Adenocarcinoma in situ may be found in the urinary bladder alone or in combination with an invasive adenocarcinoma.1677. An extremely rare variant of adenocarcinoma is the clear cell type (mesonephric). obstruction {2379}.1-7. 1677. A Low grade papillary urothelial carcinoma with intracytoplasmic lumina.660. The hepatoid type is also rare and consists of large cells with eosinophilic cytoplasm {344}. while CK-20 is reported to be positive in most bladder adenocarcinomas. High power view of intracytoplasmic lumina with mucin in a low grade urothelial carcinoma (Alcian blue pH 2.919.59 Adenocarcinoma.2791. which consists of papillary structures with cytoplasmic cells that characteristically exhibit a HOBNAIL appearance {456}.1504. Three patterns are described and these are.57 Adenocarcinoma. Another marker of interest is βcatenin. Adenocarcinoma arising in extrophy is felt to be secondary to the long-standing intestinal metaplasia common to this disease {919. 2.2898}. Finally. Fig.2629. prostate. B Immunohistochemical detection of alpha-fetoprotein in hepatoid adenocarcinoma with so-called medullary pattern. B Pseudoglandular arrangement of urothelial cells in a low grade urothelial carcinoma (H&E).1327. The mucosa is replaced by glandular structures with definitive nuclear atypia. The signet ring cell variant may be diffuse or mixed.660.

A cinoma {499}. NOS Enteric (colonictype) Signet ring cell Mucinous Clear cell Hepatoid Mixed Reference {953} {953} {257. adenocarcinoma may occur {1088. 8p (50%) and 11p (43%) in 8 schistosomiasis-associated adenocarcinomas.2612}. Chromosomal arms 3p. Cystitis glandularis is present in invasive adenocarcinoma ranging from 14. LOH of 9p likely targets the p16/p14 tumour suppressor genes. A partial allelotype reported loss of chromosomal arm 9p (50%). which harbors cystitis glandularis.953. the prognosis is poor since most adenocarcinomas present at advanced stage with muscle invasive disease and beyond (T2/T3). this spectrum of chromosomal loss is similar to urothelial and squamous cell carcinoma of the bladder. B Predictive factors Clinical factors Management of invasive adenocarcinoma of the bladder includes partial or radical cystectomy followed by consideration of chemotherapy or radiotherapy according to the extent of the lesion. 9q (17%). but this was not confirmed. With the exceptions of a lower frequency of loss of 9q and 13q. Survival at 5 years is 31% {953} -35% {551}.67% of cases {24. Some studies have suggested that nonurachal adenocarcinomas carry a worse prognosis {95.2612}. Among histologic types of adenocarci- Table 2. in patients with pelvic lipomatosis. 2. Partial cystectomy is usually associated with a relatively high recurrence rate {2853}. and proliferating cell nuclear antigen (PCNA) are associated with grade and stage of nonurachal bladder adenocarcinomas {1994}.05 Variants of adenocarcinomas of the bladder. Further support for the observation of 18q loss is provided by a study that detected LOH of the D18S61 microsatellite marker in a patient’s adenocarcinoma and urine DNA {628}. S. but its role in the pathogenesis of invasive adenocarcinoma is not clear. These tumours typically arise in the bladder base or dome.2901} {344} {953} 130 Tumours of the urinary system . The 17p LOH targets the p53 gene as a separate study reported 4/13 adenocarcinomas to have p53 point mutation {2784}. 14q and 18q also showed LOH but no loss of 13q was seen {2380}.2862}. Signet-ring carcinoma is a rare variant of mucus-producing adenocarcinoma and will often produce linitis plastica of the bladder {454}.952} {953} {456. However. and endometriosis of the bladder {2885}. few studies have examined the genetic alterations underlying adenocarcinoma of the bladder. but can occur anywhere in the bladder. B Adenocarcinoma in situ. otherwise histologic type has no prognostic significance {953}. Immunohistochemical markers Little is known about genetic factors associated with prognosis of adenocarcinoma of the bladder. Somatic genetics To date. Variant Adenocarcinomas. noma. PCNA. It is important to distinguish between urachal and non-urachal adenocarcinomas especially for treatment purposes. 4p and 4q. Adenocarcinoma may also arise in conjunction with villous adenomas. However. Morphologic factors Stage is the most important prognostic factors for this disease {953}. There is an increased incidence of local recurrence and distant metastasis in patients with a high Ki-67. Note columnar epithelium with nuclear anaplasia involving mucosal surface. Proliferation indices of markers such as the nucleolar organizer region (AgNOR). pure signet ring cell carcinoma carries the worst prognosis. Poor prognosis of this variant is associated with advanced stage at diagnosis. 17p (50%). and AgNOR proliferation index. Fig. haematobium infestation. Ki-67.61 A Adenocarcinoma in situ of urinary bladder. Primary vesical adenocarcinoma represents the most common type of cancer in patients with bladder extrophy.

followed by pain (42%). and its presence should raise the question of urachal mucous carcinoma. but it eventually becomes ulcerated as the tumour reaches the bladder cavity.1230. and these calcifications may be detected on plain X-ray films of the abdomen.1263. 1526. 2.1230. B In this illustrations of mucinous adenocarcinoma there is a row of mucin producing cells lining a fibrovascular septae. of about 1. but it may involve the route of the urachal remnants. On the other side there are signet ring cells floating within the mucinous material. and it may or may not destroy the overlying mucosa. Clinical features Hematuria is the most common symptom (71%). and the cut surface is glistening demonstrating its mucinoid appearance. less frequently in the posterior wall. light-tan appearance. Mucusuria occurs in about 25% of the cases {953}.62 Urachal adenocarcinoma of bladder.953. 1813. The urachal carcinoma is located within the wall of the bladder in the dome of the bladder. B Fig.2383.1261.1526.1813. Urachal remnants are reported to occur predominantly in the vertex or dome and the anterior wall. The presence of a mucinous adenocarcinoma containing signet ring cells floating within mucin is a very common occurrence in urachal carcinoma. forming a relatively large mass that may invade the Retzius space and reach the anterior abdominal wall. Mucinous lesions tend to calcify. A Partial cystectomy including the dome of the bladder with the Retzious space (RS). and they extend to the umbilicus {2343}. Localization Urachal carcinomas arise from the urachus. 2.1263.6 years. and connective tissue between bladder and anterior abdominal wall at umbilicus (U).2832}. This disease occurs slightly more in men than in women. with a ratio. B Total cystectomy specimen. Tamboli Definition Primary carcinoma derived from urachal remnants. The mass may be discrete.2832}. Macroscopy Urachal carcinoma usually involves the muscular wall of the bladder dome. The patient may present with the suprapubic mass.1261. tumour (T). irritative symptoms (40%). ICD-O code 8010/3 RS U T A Epidemiology Urachal adenocarcinoma is far less common than non-urachal adenocarcinoma of the bladder. and umbilical discharge (2%) {878. which is about 10 years less than that for bladder adenocarcinoma.2383. A B Fig. urothelial. Urachal carcinoma 131 . squamous and other carcinomas may also occur.953. the mean patient age is 50. reflecting its mucinous contents.63 Urachal adenocarcinoma of bladder. The cut surface of this tumour exhibits a glistening.Urachal carcinoma A. Most cases of urachal carcinoma occur in the fifth and sixth decades of life.G.8:1 {878. The vast majority of urachal carcinomas are adenocarcinomas. The mucosa of the urinary bladder is not destroyed in early stages of the disease. Ayala P. A Moderately differentiated mucinous adenocarcinoma.

(2) absence of cystitis cystica and cystitis glandularis.06 Staging system of the urachal carcinoma. and Leu-M1 {24. enteric.64 Adenocarcinoma. Pure signet ring-cell carcinoma rarely occurs in the urachus. Invasive but confined to urachus III. Urachal adenocarcinoma may be associated with cystitis cystica and cystitis glandularis. Prognosis Management of urachal adenocarcinoma consists of complete eradication of the disease. not otherwise specified. and one (4%) was a signet ring-cell carcinoma {953}. Urachal adenocarcinomas are subdivided into mucinous. Metastases to: A. Peritoneum D. Staging Although urachal adenocarcinoma has been staged as a bladder carcinoma using the TNM staging system which is difficult to apply because the majority of urachal adenocarcinomas are "muscle invasive".953}. signet ring-cell differentiation is present within a mucinous carcinoma. intestinal metaplasia of the urachal epithelium is believed to be the favoured predisposing factor {201}. Mucinous carcinomas are characterized by pools or lakes of extracellular mucin with single cells or nests of columnar or signet ring-cells floating in it.2853}. Precursor lesion The pathogenesis of urachal adenocarcinoma is unknown. (2) a sharp demarcation between the tumour and the surface epithelium. 2. Examination of the surgical margins with frozen section has been advocated {878}. Local extension to: A. Histopathology This discussion pertains mainly to adenocarcinomas as the most common. are common. Bladder muscle B. 2. Partial or radical cystectomy. The enteric type closely resembles a colonic type of adenocarcinoma and may be difficult to differentiate from it. The cells of urachal adenocarcinoma stain for carcinoembryonic antigen {24.A B Fig. and (3) exclusion of primary adenocarcinoma located elsewhere that has spread secondarily to the bladder. a characteristic finding in mucinous (colloid) adenocarcinoma of the urachus. I. these subtypes are similar to those Table 2. (3) invasion of muscle or deeper structures and either intact or ulcerated epithelium. (5) presence of a suprapubic mass. Bladder adenocarcinoma may be very difficult to rule out because it has the same histologic and immunohistochemical features as urachal adenocarcinoma does. of adenocarcinoma of the urinary bladder. signet ring-cell. however. Confined to urachal mucosa II. covered by urothelium. C Malignant cells floating in a mucin pool. who proposed the following criteria: (1) tumour in the bladder (dome). believed to be very restrictive. 12 (50%) tumours were mucinous. most commonly. These criteria. (4) presence of urachal remnants. including the resection of the umbilicus. Although a urachal adenocarcinoma may arise from a villous adenoma of the urachus {1571}. were modified by Johnson et al. In one study with 24 cases of urachal carcinoma. B Primary urachal adenocarcinoma. the cystitis cystica or cystitis glandularis must show no dysplastic changes. however. intestinal type with complex atypical glands infiltrating the bladder wall. (6) a sharp demarcation between the tumour and the normal surface epithelium. Distant sites ________ From Sheldon et al. Abdominal wall C. Other viscera IV. A Mucinous (colloid) pattern of adenocarcinoma of the urachus with its characteristic mucin pool. The 5 year survival rate has been reported to range from 25% {2813} to 61% {953}. Criteria to classify a tumour as urachal in origin were initially established by Wheeler and Hill in 1954 {2811} and consisted of the following: (1) tumour in the dome of the bladder. four (17%) were mixed. and (7) tumour growth in the bladder wall. is the treatment of choice. especially in cases in which a partial cystectomy is done {878. Regional lymph nodes B. 132 Tumours of the urinary system . and mixed types. seven (29%) were enteric. a specific staging system for this neoplasm has been proposed {2383}. because dysplastic changes of the mucosa or presence of dysplastic intestinal metaplasia would tend to exclude an urachal origin.65 Intramural urachal canal without complexity. {1230}. {2383}.953}. Recurrences. D Mucinous (colloid) pattern of adenocarcinoma of the urachus with malignat cells floating in a mucin pool. branching into the Retzius space. C D Fig. Hence.

2901}. Macroscopy Although the gross appearance is nonspecific.1954. Epidemiology Clear cell adenocarcinomas of the urinary bladder are rare. In some cases. but also malignant tumours such as urothelial carcinoma with clear cells. Patients are typically females that range in age from 22 to 83 (mean 57 years). When present. As these tumours occur more frequently in women. LeuM-1 and negative for prostate specific antigen. clear cell adenocarcinomas may be associated with urothelial carcinoma or even rarely with adenocarcinoma non-special type (NOS) {876. and some clear cell adenocarcinomas arise in a diverticulum. Cytologic atypia is usually moderate to severe.66 Clear cell adenocarcinoma variant of the urinary bladder. estrogen and progesterone receptors. Precursor lesions Occasional clear cell adenocarcinomas have been associated with endometriosis or a Müllerian duct remmant. frequently they grow as polypoid to papillary masses. Although exceptional cases have been reported to arise from malignant transformation of nephrogenic adenoma. and were designated as mesonephric adenocarcinomas despite lack of convincing evidence for a mesonephric origin. Oliva Definition Clear cell adenocarcinoma is a distinct variant of urinary bladder carcinoma that resembles its Müllerian counterpart in the female genital tract. rare cases coexisted with urothelial dysplasia. metastatic clear cell renal carcinoma. the former being the most common.2708}. These tumours show high MIB-1 activity and are often positive for p53 {876. 2. they are histologically very similar to clear cell adenocarcinomas of the female genital tract. tubulo-cystic. bladder clear cell adenocarcinomas were thought to be of mesonephric origin. a Clear cell adenocarcinoma 133 . prostate-specific acid phosphatase. Immunohistochemical studies have shown that clear cell adenocarcinomas are positive for CK7. They should be staged using the TNM system for bladder cancer. The tubules vary in size and may contain either basophilic and/or eosinophilic secretions. Histopathology Clear cell adenocarcinomas have a characteristic morphology. ed with a brisk mitotic activity {876. Histogenesis In the past. CEA. papillary and/or diffuse. frequently associatFig.876.2901}. The tumour cells range from flat to cuboidal to columnar and they may have either clear or eosinophilic cytoplasm or an admixture thereof.1954}. Hobnail cells are frequently seen but are only rarely conspicuous. showing one or more of the typical three morphologic patterns. Tumour spread and stage Clear cell adenocarcinomas may infiltrate the bladder wall and metastasize to lymph nodes and distant organs similarly to urothelial carcinomas.Clear cell adenocarcinoma E.1954. CA125. The papillae are generally small and their fibrovascular cores may be extensively hyalinized. commonly presenting with hematuria and/or dysuria {640. The differential diagnosis of clear cell adenocarcinoma includes most frequently nephrogenic adenoma. diffuse sheets of tumour cells are a minor component in most cases. cervical or vaginal clear cell adenocarcinoma or rarely adenocarcinoma of the prostate secondarily involving the bladder {1954}. CK20. and they are occasionally associated with benign Müllerian epithelium. this is a highly controversial area. ICD-O code 8310/3 Synonym Mesonephric carcinoma {2901}. a benign reactive process.

However. 134 Tumours of the urinary system . Villous adenomas of the bladder often coexist with in situ and invasive adenocarcinoma. The overall morphology of this lesion is similar to the colonic counterpart.G. Many of these tumours have an exophytic growth pattern. and their immunohistochemical profile overlaps with that of urothelial carcinoma. Cumulative experience from the literature indicates that clear cell adenocarcinoma may not be as aggressive as initially believed {85. Therefore.640}. Immunoprofile Villous adenomas of the bladder are positive for cytokeratin 20 (100% of cases). dome. range. The tumour usually occurs in elderly patients (mean age. and trigone of the urinary bladder. 65 years. nuclear hyperchromasia. carcinoembryonic antigen (89%).1954}.2356}.67 Villous adenoma of the urinary bladder (urachus) showing papillary fronds covered by columnar mucus-secreting epithelium and its characteristic nuclear crowding and pseudostratification (H&E). nuclear crowding. and occasional Epidemiology Villous adenomas of the urinary bladder are rare with fewer than 60 cases reported. they have been diagnosed in patients with a previous history of urothelial carcinoma. 2. epithelial membrane antigen (22%).876. In this setting it is presumed that aberrant differentiation which frequently occurs in high grade bladder cancer has an unusual morphology of clear cell adenocarcinoma in a small subset of patients {876. Progression to adenocarcinoma is rare. There is no apparent gender pre- prominent nucleoli. Histopathology Microscopically. The epithelial cells display nuclear stratification. they may be diagnosed at an early stage and have a relative better prognosis. Fig. High stage tumours have a poor prognosis. cytokeratin 7 (56%). Macroscopy On gross examination the lesion is a papillary tumour that is indistinguishable from a papillary urothelial carcinoma. Localization It shows a predilection for the urachus. Cheng A. consisting of pointed or blunt finger-like processes lined by pseudostratified columnar epithelium. most clear cell adenocarcinomas probably originate from peculiar glandular differentiation in urothelial neoplasms as most bladder clear cell adenocarcinomas have not been associated with endometriosis.1954}. On limited biopsy specimens there may be only changes of villous adenoma. Prognosis and predictive factors No long follow-up is available in many of these tumours. the entire specimen should be processed to exclude invasive disease. and acid mucin with alcian blue periodic acid-Schiff stain (78%) {430}. Prognosis Patients with an isolated villous adenoma have an excellent prognosis. ICD-O code 8261/0 dominance. Ayala Definition Villous adenomas is a benign glandular neoplasm of the urinary bladder which histologically mimics its enteric counterpart. Villous adenoma L.Müllerian origin is postulated for some of them {640. the tumour is characterized by a papillary architecture with central fibrovascular cores. Cystoscopic examination often identifies an exophytic tumour. 23-94 years). Clinical symptoms The patients often present with hematuria and/or irritative symptoms {430.

In some papers. plasmacytoid carcinoma and a poorly differentiated urothelial carcinoma. malignant lymphoma. scant cytoplasm and nuclei containing finely stippled chromatin and inconspicuous nucleoli. Approximately 56% of patients will present with metastatic disease at the time of diagnosis. because the presence of these differentiated areas does not contradict the diagnosis of small cell carcinoma. Other symptoms include dysuria or localized abdominal/pelvic pain {1531}.68 Neuroendocrine carcinoma of the urinary bladder. in 4. 44%. Roughly 50% of cases have areas of urothelial carcinoma {1934} and exceptionally. Histopathology All tumours are invasive at presentation {2640}. They consist of small. Mitoses are present and may be frequent. 56%. The neuronal-specific enolase is expressed in 87% of cases. squamous cell carcinoma and/or adenocarcinoma. Histogenesis In the spite of the low frequency of associated flat carcinoma "in situ" referred in the literature (14%) {2640}. nodular mass with or without ulceration.2 in 64%) expression in the small cell component supports the hypothesis of urothelial origin {60}.P. but in the majority of them. The neuroendocrine expression of this Clinical features Gross haematuria is the most common presenting symptom in patients with small cell carcinoma (SCC) of the bladder. bone. with nuclear molding. 2.7% they arise in a diverticulum {100}. The tumour may appear as a large solid. lymphoepithelioma-like carcinoma. even if neuroendocrine differentiation cannot be demonstrated. Schoenberg Definition Small cell carcinoma is a malignant neuroendocrine neoplasm derived from the urothelium which histologically mimics its pulmonary counterpart. and the stem cell theory {254}. Algaba G. and may extensively infiltrate the bladder wall. Necrosis is common and there may be DNA encrustation of blood vessels walls (Azzopardi phenomenon). A Low power view of a neuroendocrine carcinoma showing both atypical carcinoid and undifferentiated small cell features. The differential diagnosis is metastasis of a small cell carcinoma from another site (very infrequent) {608}. Somatic genetics Data obtained by comparative genomic A B Fig.2182}. and ectopic secretion of ACTH have also tumour is identified by many methods.Small cell carcinoma F. rather uniform cells. Villous adenoma / Small cell carcinoma 135 . 33%. ICD-O code 8041/3 been reported as part of the paraneoplastic syndrome associated with primary SCC of the bladder {2021. the immunohistochemical method is used. The diagnosis of small cell carcinoma can be made on morphologic grounds alone. The vesical lateral walls and the dome are the most frequent topographies. Peripheral (sensory) neuropathy may also be a clinical sign of metastatic disease and is attributed to the paraneoplastic syndrome associated with tumour production of antineuronal autoantibodies. neuroendocrine granules are found with electron microscopy or histochemical methods. and Chromogranin A only in a third of cases {2640}. This is important. Electrolyte abnormalities such as hypercalcemia or hypophosphatemia. The most common locations for disease spread include: regional lymph nodes. Sauter M. B Well differentiated neuroendocrine carcinoma characterized by cell pleomorphism and high mitotic rate. 20% {2640}. The presence of antiHU autoantibodies (IgG) is a specific marker of the paraneoplastic syndrome and should prompt careful evaluation for SCC (particularly in the lung) in a patient without a history of cancer {93}. the high frequency of cytokeratin (CAM5. liver. Localization and macroscopy Almost all the small cell carcinomas of the urinary tract arise in the urinary bladder {2640}. isolated. and lung. Other hypotheses are the malignant transformation of neuroendocrine cells demonstrated in normal bladder {60}. polypoid.

Overall prognosis has been shown to be related to the stage of disease at presentation. 4q. hybridization suggest that urinary bladder small cell carcinoma is a genetically unstable tumour. B Chromogranin A expression. 3q26. 5q. 5p. Clinical features These occur over a wide age range of 10-88 years with a mean in the forties {429. however.2081}. potentially pinpointing the location of activated oncogenes were found at 1p22-32. Paraganglioma Definition Paraganglioma of the bladder is a neoplasm derived from paraganglion cells in the bladder wall. Davis 16. have variable success {182.1845. Tumour confined to the bladder wall may have a better prognosis {100. 136 Tumours of the urinary system . The most frequent changes included deletions of 10q.1845}. They are histologically identical to paragangliomas at other sites. Genetic factors The prognostic or predictive significance of cytogenetic or other molecular changes in small cell carcinoma of the urinary bladder is unknown.236 bladder tumours (0. C Paraganglioma. High level amplifications. Age greater than 65.1587}. and 20q. A Cytoplasmatic expression of cytokeratin 5.1587}.1508. 11. 8q24 (including CMYC). and 18.70 A Paraganglioma. 9. The immunohistochemical detection of p53 (77%) failed to mark cases with a poorer prognosis {2640}. independently associated with survival {1105. ICD-O code 8680/1 Synonym Phaeochromocytoma.3.J. Chromogranin expression.06-0. The overall 5year survival rate for patients with small cell carcinoma of the bladder with local disease has been reported as low as 8% {8. They are a little more com- A B C Fig. 6p. B Paraganglioma. 2. typically exhibiting a high number of cytogenetic changes {2596}. The latter observation is based upon the theory that micrometastases are already present at the time of diagnosis in patients with clinically localized disease {1587}. The same tumour also showed a nuclear p53 accumulation. but the commonly cited incidence is 0. Complex and heterogeneous cytogenetic alterations were found in this tumour including rearrangements of the chromosomes 6. 2.2640}. Cell clusters surrounded by network of fine collagenous septa containing blood vessels and sustentacular cells in a paravesicular paraganglioma. Prognosis and predictive factors Clinical factors This tumour type is characterized by an aggressive clinical course with early vascular and muscle invasion. Administration of systemic chemotherapy and cystectomy or radiotherapy.69 Small cell carcinoma.2640}. and 12q14-21 (including MDM2) {2596}. 1062.47%).A B Fig. 13.2. Incidence These are rare tumours and by 1997 only about 200 cases had been reported {948}. Only one tumour was analyzed by cytogenetics {133}. high TNM stage and metastatic disease at presentation are predictors of poor survival.10% {1420. it has also been suggested that clinical stage is not Morphological factors No difference has been shown between tumours with pure or mixed histology. and 13q as well as gains of 8q. Intense chromogranin reaction in the tumour cells of a paraganglioma localized within the wall of the urinary bladder. In the AFIP experience there were 77 bladder paragangliomas out of C.

Invasive dispersion through the bladder wall.7%) were judged to be malignant based upon the presence of metastasis or extension beyond the bladder. Ultrastructural features include dense core neurosecretory granules.0 cm in size. Macroscopy An autopsy study has shown that paraganglia were present in 52% of cases {1115}. sweating and even syncope related to increased levels of catecholamines or their metabolites which can be found in serum or urine {1845}. and usually absent {1466}. Younger age: there were 8 cases in the second decade of life and 5 of these were malignant. sometimes with fragmentation of muscle fascicles by tumour nests. usually less then 4. Mitoses are rare. tremulousness.1280.1280}. Prognosis and predictive factors The criteria for diagnosing malignant paraganglioma are metastasis and/or "extensive local disease" {1508}. 2. recently been done (unpublished data). Four features appear to indicate an increased potential for malignant behaviour: 1. By immunohistochemistry. 4. 20% in the trigone. synaptophysin and others. A Paraganglioma with circumscribed growth pattern. bladder paragangliomas react as they do at other sites – negative for epithelial markers A B C Fig. 18% posterior wall. In some cases there may be striking resemblance to urothelial carcinoma. Micturition attacks: these were also seen in 50% of malignant cases and 12% of benign ones. usually immediately beneath the urothelium. These attacks consist of bursting headache. Hypertension: this was seen in 50% of malignant cases and 12% of the benign ones. usually having the typical morphology of catecholamine–secreting tumours with eccentric dense cores {948. Large paraganglioma adjacent to the wall of the urinary bladder.71 Paraganglioma. amphophilic or acidophilic cytoplasm and ovoid nuclei. and positive for the neuroendocrine markers – chromogranin. B Paraganglioma with dissection through the muscularis propria. 2. A recent study found that those tumours staged as T1 or T2 did not show any recurrences or metastases while those that were stage T3 or higher were at risk for both {429}. the cells are arranged in discrete nests. In about 10% of the cases. separated by a prominent vascular network. Twelve of the 72 (16. 2. C Paraganglioma with circumscribed growth pattern.mon in females by 1. 1508}. we found 38% in the dome. anxiety. Most of these are circumscribed or multinodular tumours. Cells are round with clear. 13% anterior wall and the others in the bladder neck and lateral walls. The malignant tumours usually demonstrated widespread dispersion through the bladder wall. 3. In 45 cases where the location was known. pounding sensation. A review of 72 AFIP cases accumulated since the initial 58 cases reported in 1971 {1466} has Fig. Flattened sustentacular cells can sometimes be highlighted in the periphery of the cell nests with S-100 protein. Scattered larger or even bizarre nuclei are often present {1845}. intermittent gross hematuria and "micturition attacks" is the characteristic feature {1420.4:1 {1845}. Most were in the muscularis propria and this is where most of the tumours are located. Histopathology Microscopically. the "Zellballen" pattern. Paraganglioma 137 . In one study there was an average diameter of 1. Longterm follow-up is always indicated because metastases have been known to occur many years later {948.9 cm {1420}. small neuroblast-like cells are present. Some cases have been familial. This was rarely seen in those that proved to be benign. blurred vision. They were present in any part of the bladder and at any level of the bladder wall.1845}.72 Paraganglioma of the urinary bladder. The clinical triad of sustained or paroxysmal hypertension.

The tumour cells have abundant amphophilic cytoplasm and arranged in an insular. ICD-O code 8240/3 Epidemiology Less than two-dozen cases of carcinoid tumours of the urinary bladder have been reported {343. membrane-bound. such as inverted papilloma {2485} and adenocarcinoma {449}. The tumours show immunoreactivity for neuroendocrine markers (neuron-specific enolase. followed by irritative voiding symptoms. electron-dense neurosecretory granules.480. 138 Tumours of the urinary system . Prognosis and predictive factors More than 25% of patients will have regional lymph node or distant metastasis {2527} but majority are cured by excision. 29-75 years). Coexistence of carcinoid with other urothelial neoplasia. serotonin.449. chromogranin. 1. Cheng Definition Carcinoid is a potentially malignant neuroendocrine neoplasm derived from the urothelium which histologically is similar to carcinoid tumours at other locations.Carcinoid L.8:1). An organoid growth pattern. The tumour often presents as a polypoid lesion upon cystoscopic examination.1068. Ultrastructural examinations demonstrate characteristic uniform.2768. Flow cytometric studies revealed an aneuploid cell population in one case {2768}. nested variant of urothelial carcinoma and metastastic prostatic carcinoma. Clinical features Hematuria is the most common clinical presentation. The tumours are positive for the argyrophil reaction by Grimelius silver stains and argentaffin reaction by Fontana-Masson stains. and tumour necrosis is absent. Histopathology Carcinoid tumours of the bladder are histologically similar to their counterparts in other organ sites.2485. trabecular. Differential diagnosis This includes paraganglioma. can be appreciated. 2527. range. with slight male predominance (the male-to-female ratio. The tumour usually occurs in elderly patients (mean age. has been reported. or pseudoglandular pattern in a vascular stroma. 56 years. and synaptophysin) and cytokeratin (AE1 and 3). and range in size from 3 mm-3 cm in the largest dimension. acini.2865}. The nuclei have finely stippled chromatin and inconspicuous nucleoli. One case arose in an ileal neobladder {803}. Mitotic figures are infre- quent. Macroscopy The tumours are submucosal with a predilection for the trigone of the bladder. Association with carcinoid syndrome has not been reported. resembling that seen in paraganglioma. round.

Carcinoid / Rhabdomyosarcoma 139 . Staining for myosin and myoglobin can be negative because it is usually found only in well differentiated tumour cells.1404}.73 Embryonal rhabdomyosarcoma. Histopathology Tumour cells of embryonal rhabdomyosarcoma are usually small. Desmin and pan-actin (HHF35) can also be detected in almost all rhabdomyosarcomas but it is not specific. Leuschner Definition Rhabdomyosarcoma is a sarcoma occurring in the urinary bladder that recapitulates morphologic and molecular features of skeletal muscle. Recurrences of embryonal rhabdomyosarcoma can show a very high degree of differentiation forming round myoblasts. Deeper parts of the tumours are often hypocellular. This is assumed to be specific for a skeletal muscle differentiation. botryoid subtype of embryonal rhabdomyosarcoma is the end of a spectrum of polypoid growing embryonal rhabdomyosarcomas sharing a similar favourable prognosis {1482}. Some cells may have classic rhabdomyoblastic appearance with abundant eosinophilic cytoplasm and cross striations. Immunohistochemically. 2. round cells. Highly differentiated tumour cells can lack myogenin expression. often set in a myxoid stroma.Rhabdomyosarcoma I. Botryoid subtype of embryonal rhabdomyosarcoma has a condensation of tumour cells beneath the covering surface epithelium. In adults rhabdomyosarcoma is rare and usually of the pleomorphic type. Macroscopy Growth pattern of embryonal rhab- Fig. Fig. Primarily deep invasive growing tumours of the urinary bladder wall have usually a low degree of differentiation and are associated to a similar worse prognosis as seen for embryonal rhabdomyosarcoma of prostate. Almost all bladder rhabdomyosarcomas are of embryonal subtype. called the cambium layer. mostly intraluminal tumours associated with a favourable prognosis (botryoid subtype) and deeply invasive growing tumours involving the entire bladder wall and usually adjacent organs showing a worse prognosis. ICD-O code 8900/3 domyosarcoma in urinary bladder has two basic forms with prognostic impact: polypoid. the tumour cells express myogenin (myf4) and MyoD1 in the nucleus {612.74 Rhabdomyosarcoma of the bladder. The Epidemiology They are the most common urinary bladder tumours in childhood and adolescence. 2. whereas the genetically distinct alveolar subtype is extremely rare in this site {1887}.

2. and are negative for epithelial markers {1410. 140 Tumours of the urinary system .Leiomyosarcoma J. Prognosis Although previous reports suggest that 5-year survival after partial or radical cystectomy approaches 70%. High grade leiomyosarcoma frequently exhibits gross and microscopic necrosis. Several cases of leiomyosarcoma of the bladder have occurred years after cyclophosphamide therapy {2039.2253}.76 Bladder leiomyosarcoma. Fig. and lack of cytologic atypia {1639}. Males are more frequently affected than females by over 2:1 {1639. Sarcomatoid carcinoma can resemble leiomyosarcoma but is usually associated with a malignant epithelial component or exhibits cytokeratin positivity. high grade leiomyosarcoma shows marked cytologic atypia.2543}. and on occasion. low cellularity. and has mitotic activity less than 5 mitoses per 10 HPF. Fig. and very rarely can involve the ureter or renal pelvis {947.1734. abnormal mitoses. Low grade leiomyosarcoma exhibits mild to moderate cytologic atypia.2817}. myxoid change can occur in leiomyosarcoma {2899}. Clinical features The vast majority of patients present with haematuria. leiomyosarcoma stains with antibodies directed against actin. and most cases have greater than 5 mitoses per 10 HPF.75 Leiomyosarcoma of the bladder. abdominal pain or urinary tract obstruction may be present. This sarcoma occurs primarily in adults in their 6th to 8th decade.1639. desmin and vimentin. circumscription.2889}. the largest recent study indicates that 70% of patients with leiomyosarcoma developed recurrent or metastatic disease. However. 1734. and an arrangement in compact cellular fascicles in contrast to reactive spindle cell proliferations. ICD-O code 8890/3 pelvic mass. Grading of leiomyosarcoma is based on the degree of cytologic atypia. Reactive spindle cell proliferations such as inflammatory pseudotumour or postoperative spindle cell nodule/tumour can be difficult to distinguish from leiomyosarcoma {1572. Localization Leiomyosarcoma can occur anywhere within the bladder. Macroscopy Leiomyosarcoma of the urinary bladder is typically a large. 2. 1816}. infiltrating mass with a mean size of 7 cm. Cheville Definition Leiomyosarcoma is a rare malignant mesenchymal tumour that arises from urinary bladder smooth muscle. Leiomyosarcoma exhibits greater cytologic atypia. Immunohistochemically. which have a loose vascular myxoid background. In contrast. a palpable arated from leiomyosarcoma based on its small size. Histopathology Histopathologic examination reveals a tumour composed of infiltrative interlacing fascicles of spindle cells. Leiomyoma can be morphologically sep- Epidemiology and etiology Although leiomyosarcoma is the most common sarcoma of the urinary bladder it accounts for much less than 1% of all bladder malignancies. resulting in death in nearly half {1639}.

and tumours occur positive. either for gynecologic malignancies or prostate cancer {699. Most tumours exhibit local or distant extension beyond the bladder at the time of diagnosis. Some angiosarcomas have solid areas. The only epithelioid angiosarcoma of the urinary bladder reported to date was negative for cytokeratin. Urinary haemangioma lacks cytologic atypia and the anastomosing and solid areas of angiosarcoma.2866}. 2. all as case reports {699}. Prognosis Urinary bladder angiosarcoma is a very aggressive neoplasm. Histopathology Histopathologic features consist of anastomosing blood-filled channels lined by cytologically atypical endothelial cells. Patients present with hematuria. and epithelioid features can be present {2322}. Pyogenic granuloma is another benign vascular proliferation that very rarely occurs in the bladder. but some epithelioid angiosarcomas at other sites can be cytokeratin Clinical features Only 10 cases of urinary bladder angiosarcoma have been reported. Angiosarcoma must be distinguished from haemangioma of the bladder.Angiosarcoma J. high grade urothelial carcinoma can mimic angiosarcoma but the identification of a clearly epithelial component as well as immunohistochemistry can be diagnostic {2085}. Males are more frequently affected than females. Fig. Leiomyosarcoma / Angiosarcoma 141 . Kaposi sarcoma may involve the urinary bladder and should be considered in the differential diagnosis. Haemangioma of the bladder is typically small (usually less than 1 cm). and approximately a third of cases are associated with prior radiation to the pelvis. and approximately 70% of patients die within 24 months of diagnosis {699}. CD31 expression. and nearly 80% are of the cavernous type {431}. especially in immunocompromised patients {2183. Macroscopy Angiosarcoma of the bladder is typically a large tumour but can be as small as 1 cm. ICD-O code 9120/3 in adults with a mean age at diagnosis of 55 years. Urinary bladder angiosarcoma stains positively with the immunohistochemical markers of endothelium including CD31 and CD34. and is composed of closely spaced capillaries lined by bland endothelium which may show mitotic activity {90}.77 Angiosarcoma of urinary bladder. Rarely. Cheville Definition Angiosarcoma of the urinary bladder is a very rare sarcoma that arises from the endothelium of blood vessels.1874}.

Variably calcified.2900}.2900}. especially in the trigone region {2900}. often deeply invasive. Pelvic pain and/or palpable abdominal mass are less frequent. Foci of chondrosarcomatous differentiation and/or spindle cell areas may also be observed {215. Histopathology Histologically. The stage of the disease at diagnosis is the best predictor of survival.Osteosarcoma L. A few patients had concurrent urinary schistosomiasis {2900}. which is the most important differential diagnosis.863. secondary infection. uremia. Clinical features Haematuria. etc. A recognizable malignant epithelial component should be absent. with an average age of 60-65 years {215. and recurrent urinary tract infections are the most common presenting symptoms. Macroscopy Osteosarcoma of the urinary bladder typically presents as a solitary.5 cm) {215.2900}. gritty. variably haemorrhagic mass.78 Osteosarcoma of the urinary bladder. Anecdotal cases have been reported in the renal pelvis {655}.2900}. Localization Most osteosarcomas occurred in the urinary bladder. Tumour size varies between 2 and 15 cm (median: 6. 2. large. the tumour is a high grade. ICD-O code 9180/3 Epidemiology Most osteosarcomas of the urinary bladder occurred in male patients (male to female ratio: 4:1). Prognosis Osteosarcoma of the urinary tract is an aggressive tumour with poor prognosis. woven bone lamellae are rimmed by malignant cells showing obvious cytologic atypia (as opposed to stromal osseous metaplasia occurring in some urothelial carcinomas {655}). Abundant trabeculae of neoplastic bone surrounded by a malignant spindle cell component. Metastases often occurred late in the course of the disease. Etiology One case of bladder osteosarcoma occurred 27 years after radiation therapy for urothelial carcinoma {754}.) {863. allowing discrimination from sarcomatoid carcinoma {2057}. A majority of patients have advanced stage (pT2 or higher) disease at presentation and die of tumour within 6 months.863. bone-producing sarcoma. mainly in lungs {215. Guillou Definition A malignant mesenchymal tumour showing osteoid production. most from the effects of local spread (urinary obstruction. dysuria.2900}. Fig. urinary frequency. polypoid. 142 Tumours of the urinary system .

B Pleomorphic giant cells are a common finding in this high grade. showing its characteristic storiform growth pattern and histologically normal urothelium (right bottom). Prognosis The rarity of malignant fibrous histiocytoma makes it difficult to assess the biologic behaviour of these tumours. and stains positively for the immunohistochemical markers of epithelial differentiation such as cytokeratin {1038. In contrast. D Virtually all proliferating cells in this case of malignant fibrous histiocytoma displayed immunorreactivity with anti-vimentin antibody. Reactive spindle cell proliferations lack the cytologic atypia of malignant fibrous histiocytoma. ICD-O code 8830/3 Synonym Undifferentiated high grade pleomorphic sarcoma. Malignant fibrous histiocytoma must be separated from sarcomatoid urothelial carcinoma as well as reactive spindle cell proliferations of the bladder. and pleomorphic {809.2038}. malignant fibrous histiocytoma of the bladder appears aggressive with high local recurrence rates and metastases similar to malignant fibrous histiocytoma at other sites {809}. from the limited reports. systemic chemotherapy and external beam radiation. Histopathology All subtypes of malignant fibrous histiocytoma have been described involving the bladder including myxoid. pleomorphic type. Treatment consists of resection. and can stain for alpha-1-antichymotrypsin. Clinical features Patients present with haematuria. The only patient with myxoid malignant fibrous histiocytoma of the bladder has been free to tumour following surgical resection. and is most common in patients in their 5th to 8th decade. storiform-fascicular. Epidemiology Malignant fibrous histiocytoma is one of the most frequent soft tissue sarcomas.Malignant fibrous histiocytoma J. malignant fibrous histiocytoma. A B C D Fig. C Some pleomorphic cells proliferating in this malignant fibrous histiocytoma were immunorreactive with Anti-Alpha-1-Antitrypsin antibody. local radiation and systemic chemotherapy for 3 years {809}. most malignant fibrous histiocytomas are large but tumours as small as 1 cm have been reported. Cheville Definition Malignant fibrous histiocytoma (MFH) is a malignant mesenchymal neoplasm occurring in the urinary bladder composed of fibroblasts and pleomorphic cells with a prominent storiform pattern. and in some series.1410.1555. It is difficult to determine the incidence of urinary bladder malignant fibrous histiocytoma as it is likely that several tumours previously reported as malignant fibrous histiocytoma are sarcomatoid urothelial carcinoma. How- ever. 2. malignant fibrous histiocytoma is negative for cytokeratin. Macroscopy Similar to other sarcomas of the urinary bladder.1935}. Malignant fibrous histiocytoma more frequently affects men. the second most frequent sarcoma of the urinary tract in adults {1410}. inflammatory.79 Malignant fibrous histiocytoma. and CD68. Osteosarcoma / Malignant fibrous histiocytoma 143 . A Pleomorphic type. The much more commonly encountered sarcomatoid urothelial car- cinoma can be associated with a malignant epithelial component.

ICD-O code 8890/0 Epidemiology Leiomyoma of the urinary bladder is the most common benign mesenchymal neoplasm of the urinary bladder {908. Prognosis Patients are treated by transurethral resection for small tumours. and lack necrosis. although the number of cases is small. and follow-up has been short term in several cases. B Lobulated giant leiomyoma. Tumours up to 25 cm have been reported {908}.Leiomyoma J. Dilated vessels reminiscent of haemangiopericytoma are present. The diagnosis of primary liposarcoma and malignant peripheral nerve sheath tumour of the bladder requires that bladder involvement by direct extension from another site be excluded. lack of mitotic activity Other non-epithelial tumours Malignant mesenchymal neoplasms such as malignant peripheral nerve sheath tumour. 2. and open segmental resection for larger tumours. but all solitary fibrous tumours of the bladder have had a benign course. 144 Tumours of the urinary system . chondrosarcoma and Kaposi sarcoma can very rarely involve the bladder {1410}.1338}. There is a wide age range from children to the elderly.81 Solitary fibrous tumour of urinary bladder. Histopathologic features include spindle cells arranged haphazardly in a variably collagenous stroma. Surgical removal is curative in all cases. 2. Solitary fibrous tumour of the bladder of the urinary bladder has recently been recognized {159. Leiomyoma of the bladder is circumscribed with low cellularity. size less than 2 cm {1338}. The tumour is typically a polypoid submucosal mass. J. sarcomatoid carcinoma must be excluded.502. Solitary fibrous tumour of the bladder occurs in older patients who present with pain or haematuria. In the case of primary bladder osteosarcoma and chondrosarcoma. Grossly. They are immunoreactive to smooth muscle actin and desmin. liposarcoma.2808}. but the vast majority of patients are middle-aged to older adults. B and bland cytologic features {1639}. the tumours are circumscribed. 1255. Clinical features Patients present most frequently with obstructive or irritative voiding symptoms. Macroscopy Most leiomyomas are small with a mean A Fig. Histopathology Histopathological features include well formed fascicles of smooth muscle. and occasionally haematuria. Two of the seven cases that have been reported were incidental findings {2808}. firm. Solitary fibrous tumour at other sites can act in an aggressive manner. there is a predominance of females {908}.80 A. Cheville Definition A benign mesenchymal tumour occurring in the bladder wall showing smooth muscle differentiation. Unlike sarcomas of the bladder. Cheville Fig.

I. Neurofibroma Definition A benign mesenchymal tumour occurring in a urinary bladder wall consisting of a mixture of cell types including Schwann cell. Fig. Prognosis Long-term urinary complications include bladder atony. Clinical signs include hematuria. and involvement of the bladder pseudotumour. 2351. Prognosis To date. and the male-tofemale ratio is 2. Macroscopy The tumours frequently are transmural.1737}. and recurrent urinary tract infection with hematuria. postoperative spindle nodule.1752.2881}. A congenital granular cell tumour of the gingiva with systemic involvement including urinary bladder has been reported {2011}. Leiomyoma / Other non-epithelial tumours / Granular cell tumour / Neurofibroma 145 . Atypical neurofibromas lack mitotic figures or appreciable MIB-1 labeling. ICD-O code 9580/0 Macroscopy The tumours are usually solitary.1821. It is critical to distinguish neurofibrooma of atypical or cellular type from malignant peripheral nerve sheath tumour. The tumours typically occur in young patients with neurofibromatosis type 1. Adequate sampling is critical when increased cellularity is noted in superficial biopsies.3:1 {434}. S-100 protein can be identified in the tumour cells {2490}. variably collagenized matrix. and rhabdomyosarcoma. The urinary bladder is the most common site of genitourinary involvement in neurofibromatosis. The finding of rare mitotic figures in a cellular neurofibroma is not sufficient for a diagnosis of malignancy {434}. irritative voiding symptoms. Cellular neurofibromas lack significant cytologic atypia or mitotic figures. The 11 cases reported in the literature and the 2 cases in the Bladder Tumour Registry of the Armed Forces Institute of Pathology occurred in adult patients from 23-70 years of age {88. and pelvic mass. Neurofibroma of the bladder is characterized by a proliferation of spindle cells with ovoid or elongate nuclei in an Alcian blue positive. showing a diffuse or plexiform pattern of growth. The mean age at diagnosis is 17 years.779.82 Granular cell tumour of the urinary bladder. inflammatory L.Granular cell tumour Definition A circumscribed tumour consisting of nests of large cells with granular eosinophilic cytoplasm due to abundant cytoplasmic lysosomes. Differential diagnostic considerations include low grade malignant peripheral nerve sheath tumour. Only 4 tumours (7%) underwent malignant transformation. leiomyoma. 2. fewer than 60 cases have been reported. Histopathology Microscopically. the tumours are usually of the plexiform and diffuse type.1949. ICD-O code 9540/0 is often extensive. Histopathology Histologically. perineurial like cells and fibroblasts. only one malignant granular cell tumour of the bladder has been described {2153}. There is no gender predilection. Cytoplasmic processings of tumour cells are highlighted on immunostaining for S-100 protein. neurogenic bladder. well circumscribed and vary in size up to 12 cm.1631. none of these occurred in children {434. leiomyosarcoma. necessitating cystectomy in approximately one-third of cases. Clinical features Patients typically exhibit physical stigmata of neurofibromatosis type 1.A. Cheng Epidemiology Neurofibromas of the urinary bladder occur infrequently. Sesterhenn Epidemiology This tumour is rarely seen in the urinary bladder. the cells have abundant granular eosinophilic cytoplasm and vesicular nuclei.

7:1 {431}.N. failure to find a regressed melanoma of the skin with a Woods lamp examination. Cheng Epidemiology It may be associated with the KlipelTrenaunnay-Weber or Sturge-Weber syndromes {1000. These tumours are morphologically identical to their counterparts in other organ sites. cystoscopic findings of a sessile. Histopathology Three histologic types of haemangiomas are reported. ICD-O code 9120/0 Macroscopy The tumour has a predilection for the posterior and lateral walls.1474}. Clinical features Patients often present with macroscopic hematuria and cystoscopic findings are usually non-specific. Histopathology Microscopically. Cavernous haemangioma is more common than capillary and arteriovenous haemangiomas. However.1000. Exuberant vascular proliferation may be observed in papillary cystitis and granulation tissue. Fig. 2. as metastatic tumour. L. follow up of those alive at the time of the report has been less than 2 years. Haemangioma is distingioma. Their sizes ranged from less than 1 cm to 8 cm. the great majority of tumours have shown classic features of malignant melanoma: pleomorphic nuclei. 146 Tumours of the urinary system . which is not seen or is less pronounced in haemangioma. A few of the tumours have been associated with melanosis of the vesical epithelium {1300}. Eble Epidemiology Melanoma primary in the bladder has been reported in less than twenty patients {1303}. ICD-O code 8720/3 Macroscopy Almost all of the tumours have appeared darkly pigmented at cystoscopy and on gross pathologic examination. The mean age at presentation is 58 years (range. 17-76 years). the male/female ratio of is 3.1098. J. Immunohistochemical procedures have shown positive reactions with antibodies to S-100 protein and with HMB-45. and melanin pigment. Histogenesis Haemangioma of the urinary bladder arises from embryonic angioblastic stem cells {431. Pigment production is variable and may be absent. the cystoscopic differential diagnostic considerations for pigmented raised lesions include endometriosis. One arose in a bladder diverticulum. and sarcoma. and the same criteria should be used for the diagnosis. Clinical features Gross hematuria is the most frequent presenting symptom but some have presented with symptoms from metastases {2550}. spindle and polygonal cytoplasmic contours. Accurate diagnosis requires biopsy confirmation. The generally accepted criteria for determining that melanoma is primary in the bladder are: lack of history of a cutaneous lesion.Haemangioma Definition Haemangioma of the urinary bladder is a rare benign tumour that arises from the endothelium of blood vessels. Prognosis Two-thirds of the patients have died of metastatic melanoma within 3 years of diagnosis. more frequently. Electron microscopy has shown melanosomes in several of the tumours. and pattern of spread consistent with bladder primary. multiloculated mass are highly suggestive of haeman- guished from angiosarcoma and Kaposi sarcoma by its lack of cytologic atypia and well circumscribed growth. the lesion is non descript but may be haemorrhagic. blue.83 Melanoma in situ extending into bladder from vagina.1474}. All have been adults and men and women have been equally affected.1098. one example of clear cell melanoma has been reported. but these lesions contain prominent inflammation cells. failure to find a different visceral primary. Malignant melanoma Definition Malignant melanoma is a malignant melanocytic neoplasm which may occur in the urinary bladder as a primary or. melanoma.

1947}. urinary frequency. shows a slight male predominance and may occur in children {885. Hodgkin lymphoma {1243. bladder and urethra.1692. Chronic cystitis is regularly encountered in MALT lymphoma of the bladder {1297.106. Etiology The etiology of urinary tract lymphomas is unclear.2360} have been reported.1040.1402.2635}. low grade MALT. Secondary lymphoma of the bladder is common (1220%) in advanced stage systemic lymphoma. Clinical features The most frequent symptom of urinary tract lymphomas is gross hematuria.1623} and plasmacytomas {398.2034. Epidemiology Lymphomas constitute about 5% of nonurothelial tumours of the urinary tract. Primary urinary tract lymphomas are confined to the urinary tract. primary MALT lymphoma {1018}. but common in secondary urinary tract lymphomas.1297. 1297}. In the urethra.1946} Burkitt {1946} and Hodgkin lymphoma {1702.Lymphomas A.1946}. affect mainly females (65-85%) and occur at an age of 12 . respectively) {1297}. More than 90% affect the bladder {1730}. and weight loss or ureteral obstruction with hydronephrosis and renal failure occur almost only in patients with secondary urinary tract lymphomas due to retroperitoneal disease. Marx Definition Malignant lymphoma is a malignant lymphoid neoplasm which may occur in the urinary bladder as a primary or part of a systemic disease. but less frequently (20%) in other lymphomas {1946}. Posttransplant lymphoproliferative disease restricted to the ureter allograft may occur after renal transplantation {591.85 (median 60) years. constituting less than 1% of bladder neoplasms {86. followed by dysuria. Histopathology Among primary urinary tract lymphomas. Antecedent or concurrent MALT lymphomas in the orbit {1297} and stomach {1396}. In the urethra. Reactive germinal centers are consistently present while lymphoepithelial lesions occur in only 20% of cases associated with cystitis cystica or cystitis glandularis.530}. Fig. several diffuse large B-cell lymphomas {1040} and single mantle cell {1259} and T-cell NOS lymphomas {1257} and plasmacytoma {1473} were described. 2. followed by follicular. Histogenesis (postulated cell of origin) The histogenesis of urinary tract lymphomas is probably not different from that of other extranodal lymphomas. and papillary urothelial tumours rarely occur {2034}. lymphomas often present as a caruncle {127}. Somatic genetics and genetic susceptibility Genetic findings specific to urinary tract lymphomas have not been reported Prognosis and predictive factors Primary MALT of the urinary tract has an excellent prognosis after local therapy with virtually no tumour-related deaths {127. diffuse large B-cell lymphoma is the single most frequent histological subtype.6 year.1730} are very rare. while secondary lymphoma results from disseminated lymphoma/leukaemia.1946.1035} and posttransplant lymphoproliferative disease {591. like Burkitt lymphoma {1692}. ureter.2793}.2793} and urethra {127. Frankly haemorrhagic changes have been observed {637}.2034. night sweats. Lymphoma of the ureter may form nodules or a diffuse wall thickening. In one series only 20% of cases were primary lymphomas {1297}. comparable to patients with advanced lymphomas of respective histological type elsewhere.2034}. Ulceration is rare (<20%) in primary. "Nonlocalized lymphomas" and secondary [recurrent] lymphomas of the bladder have a worse prognosis (median survival 9 years and 0. In the ureter and renal pelvis. Schistosomiasis was associated with a T-cell lymphoma of the bladder {1820}. Macroscopy Bladder lympomas may form solitary (70%) or multiple (20%) masses or diffuse thickening (10%) of the bladder wall.1946. mantle cell {1297. small cell. EBV and HIV infection have been reported in rare high grade urinary tract lymphoma (UTL) {1257. Fever. Haemangioma / Malignant melanoma / Lymphomas 147 .2793}. 398.2360}. Among secondary urinary tract lymphomas. Urinary tract lymphomas affect the renal pelvis. low grade MALT lymphoma is the most frequent in the bladder {27.47. Secondary bladder lymphoma as the first sign of disseminated disease is termed "nonlocalized lymphoma" with a much better prognosis than "secondary [recurrent] lymphoma" in patients with a history of lymphoma {1297}.84 Follicular lymphoma of urinary bladder. nocturia and abdominal or back pain {1297. Primary lymphomas of the bladder {1297. diffuse large Bcell lymphoma {238. 1402.1414} are rare. T-cell lymphoma {1820}.1040.1297. Other bladder lymphomas.

Localization The most frequent locations of metastases to the urinary bladder are the bladder neck and the trigone. A B Fig. breast. However. direct extension of colonic carcinomas to the bladder are most frequent at 21%.86 Metastic breast cancer to urinary bladder. Multifocality and prominent vascular involvement in tumours with unusual morphology should raise suspicion of metastatic tumours. and lung at 2. Grignon E. and uterine cervix (11%). skin. Ayala D. tumours with less characteristic histological features.2777}.J. followed by carcinomas of the prostate (19%). non-urothelial tract neoplasm. 2. such as malignant lymphomas.2415. or prostatic adenocarcinomas may be diagnosed by routine microscopy. Oliva J.I.5-4% {184}. Much less frequent is metastatic spread to the urinary bladder of neoplasias of the stomach. malignant melanomas. Epstein Definition Tumours of the urinary bladder that originate from an extravesical. Clinical features Metastases or. poorly or undifferentiated high grade tumours require immunohistochemical work-up {849.G. 148 Tumours of the urinary system . Histopathology Some metastatic or secondary tumours. 2708. Fig. Macroscopy The lesions may mimic a primary urothelial carcinoma or may manifest as multiple nodules. Helpap A. rectum (12%). leukemias.85 A Metastatic prostate cancer to urinary bladder. in most cases.Metastatic tumours and secondary extension in urinary bladder B. B Metastatic colon cancer to urinary bladder.1954. 2.

A B C D Fig. C Prostatic carcinoma with neuroendocrine features. D Well differentiated carcinoma of the prostate infiltrating the bladder.87 Metastatic tumours to the urinary bladder. 2. Metastatic tumours and secondary extension in urinary bladder 149 . A Well differentiated adenocarcinoma of the colon infiltrating the bladder. B Moderately differentiated colonic adenocarcinoma infiltrating the bladder with extensive areas of necrosis.

Tyczynski Definition Benign and malignant tumours arising from epithelial and mesenchymal elements of the renal pelvis and ureter. Amin F.4% of tumours of lower urinary tract and 0. A 150 Tumours of the urinary system B Fig. Epidemiology of urothelial renal pelvis cancer Renal pelvis is a part of the lower urinary tract. Haematuria and flank pain are the chief presenting symptoms. As with bladder cancer. Tumours of renal pelvis are rare.1%. ureter and multifocality is frequent {1655}. Fig.E. urinary bladder and urethra. B CT tumour renal pelvis. In females. by sex and continents. Delahunt M. tumours of the ureter and renal pelvis are more common in older patients with a mean age of incidence of 70 years {1834}.90 Pelvic urothelial carcinoma.7 to 1 with an increasing incidence in females. From D.89 Tumours of the ureter and renal pelvis. which consists also of ureter.88 Renal pelvis cancer. Corresponding figures for North America are 2. Epidemiology Tumours of the ureter and renal pelvis account for 8% of all urinary tract neoplasms and of these greater than 90% are urothelial carcinomas {1582}.Tumours of the renal pelvis and ureter B. Hartmann J.7% and 0. {2016}.B. The incidence of these tumours is 0. cancer of the renal pelvis Malignant epithelial tumours Urothelial neoplasms Clinical features Malignant tumours of the pelvicalyceal system are twice as common as those of the Fig. urothelial tumours develop at other sites {183}.1% of all cancers in Europe. As in the urinary bladder. There is a male to female ratio of 1. they constitute 2. a majority of renal pelvis tumours are urothelial carcinomas. 2. In males. {602}. Hofstädter A. 2.M. Parkin et al.000 and has increased slightly in the last 30 years. A IVP tumour renal pelvis. Incidence of cancer of the renal pelvis.7 to 1. 2. .1 per 100. 80% of tumours arise following diagnosis of a bladder neoplasm {1910} and in 65% of cases.

c) with cytological atypia. polypoid. the highest incidence rates were noted in New South Wales and Queensland in Australia (1. Etiology of urothelial renal pelvis cancer Tobacco smoking Similar to cancers of the urinary bladder.92 Tumours of the ureter and renal pelvis. and confirmed by several authors {1215. Inverted papillary urothelial carcinoma of the ureter with mutator phenotype. Japan (1. Although limited information is available about changes of renal pelvis cancer in time. as well as to asphalt and tar {1215}. Tumours of the renal pelvis and ureter 151 . Fig.1681}. and in Mallorca.41/105). Other risk factors include papillary necrosis. 1227.95/105).65/105).2245}. the main risk factor for renal pelvis tumours is tobacco smoking {1680}.79/105). 2. In females. as well as with Fig. petrochemical and plastic industries. Balkan nephropathy.makes 4. 2. B Inverted papillary urothelial carcinoma of the ureter with mutator phenotype.03/105 respectively). USA (0.79/105) {2016}. The risk increases with increasing lifetime consumption. available data from US show that in 1970s and 1980s renal pelvis cancer incidence rates rose by approximately 2. Ferrara Province in Italy (1. Spain (1. Use of analgesics increases risk of renal pelvis tumours by 4-8 times in males and 10-13 times in women.2% and 0. Hiroshima. and is similar in both sexes {1215. The highest risk was found for workers of chemical. Analgetics Another proven risk factor for cancer of the renal pelvis is long-term use of analgesics. and also exposed to coke and coal. increasing intensity of smoking. urinary tract infections or stones {922.38/105). even after elimination of the confounding effect of tobacco smoking {1668. particularly phenacetin.1680.2245}. Macroscopy Tumours may be papillary.07% respectively in North America. Louisiana (among Blacks).1583}.07% of all cancers in Europe. 2. Occupational exposure Several occupations and occupational A B Fig. Denmark (0. exposures have been reported to be associated with increased risk of renal pelvis tumours {1215}. The highest rates in males in 1990s were observed in Denmark (1.2% per year in both males and females {602}. and Iceland (0. and 5. A Partly papillary predominamtly inverted growth pattern (a. thorium containing radiologic contrast material.93 Tumours of the ureter and renal pelvis. The highest incidence rates of renal pelvis tumours are observed in Australia.1260.1681.6% of lower urinary tract tumours and 0. while the lowest rates are noted in South and Central America and in Africa. North America and Europe.34 and 1.45/105). The relationship between tobacco smoking and renal pelvis tumours was reported already in 1970s {2324}.91 Ureter urothelial carcinoma.

unusual morphology or undifferentiated carcinoma with conventional invasive poorly differentiated carcinoma is frequent.2662}.2197. Hydronephrosis and stones may be present in renal pelvic tumours while hydroureter and/or stricture may accompany ureteral neoplasms.95 Tumours of the ureter and renal pelvis. clear cell and plasmacytoid) and poorly differentiated carcinoma (lymphoepithelioma-like. indicating a molecular pathway of carcinogenesis that is similar to some mismatch repair-deficient colorectal cancers. are seen in advanced invasive tumours {321. Urothelial carcinomas of the upper urothelial tract occur in the setting of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (Lynch syndrome II) {251}. unusual morphology (nested.1032}. micropapillary. 2. causing thickening of the wall. Survival for patients with pTa/pTis lesions is essentially 100%. Genetic susceptibility Familial history of kidney cancer {2245} is generall considered a risk factor.96 Lymphoepithelioma-like urothelial carcinoma of the ureter.1507}. 152 Tumours of the urinary system .2706}.993. Mutations in genes with repetitive sequences in the coding region (TGFβRII. Some tumours distend the entire pelvis while others ulcerate and infiltrate. MLH1 or MSH6 {251. 2.399. A potential pitfall is that.2554} and frequent deletions at 17p in addition to p53 mutations. while involvement of the renal parenchyma is categorized as a pT3 tumour. bax. A high grade tumour may appear as an ill defined scirrhous mass that involves the renal parenchyma. Tumours with microsatellite instabil- ity have significantly different clinical and histopathological features including low tumour stage and grade. some tumours that invade the muscularis (pT2) may show extension into renal tubules in a pagetoid or intramucosal pattern and this should not be designated as pT3. 2. MSH3. microcystic. carcinoma-in-situ and invasive carcinoma. Prognosis and predictive factors The most important prognostic factor is tumour stage and for invasive tumours the depth of invasion. ulcerative or infiltrative. Deletions on chromosome 9p and 9q occur in 5075% of all patients {734. Slight differences based on anatomical distinctions exist in the pT3 designation of renal pelvis and ureteral tumours.993}. Concurrence of aberrant differentiation. Fig.2197}. low grade papillary carcinoma or high grade papillary carcinoma). Multifocality must be assessed in all nephroureterectomy specimens. ureter and urinary bladder share similar genetic alterations {734.1032. Tumour staging There is a separate TNM staging system for tumours of the renal pelvis and ureter {944. Fig.nodular. mimicking a primary renal epithelial neoplasm. Genetics Urothelial carcinomas of the renal pelvis. Grading The grading system for urothelial tumours is identical to that employed for bladder tumours. Microsatellite instability in 4 markers of the consensus Bethesda panel {264}. Fig.727. Inset shows cytokeratin AE1/AE3 immunostain.94 Loss of expression of the DNA mismatch repair gene MLH1 in an area of low grade urothelial dysplasia. papillary and frequently inverted growth pattern and a higher prevalence in female patients {1028. sarcomatoid and giant cell) {355. 656. MSH6) are found in 20-33% of cases with MSI. 20-30% of all upper urinary tract cancers demonstrate microsatellite instability and loss of the mismatch repair proteins MSH2. The entire morphologic spectrum of vesical urothelial carcinoma is seen and tumour types include those showing aberrant differentiation (squamous and glandular). Histopathology The basic histopathology of renal pelvis urothelial malignancies mirrors bladder urothelial neoplasia and may occur as papillary non-invasive tumours (papillary urothelial neoplasm of low malignant potential.

Squamous cell carcinoma Squamous cell carcinoma is more common in the renal pelvis than in the ureter. often occur concurrently.746. while localized pelvic plasmacytoma has been reported {1165}. Renal pelvic and ureteric leiomyoma. Non-epithelial tumours of renal pelvis and ureter Few cases of ureteric phaeochromocytoma have been reported {128}. covered by normal transitional epithelium.2727. osteosarcoma. Other Rare cases of sarcomatoid carcinoma of the pelvis and ureter can show either homologous or heterologous stromal elements {621. Small cell carcinoma of the renal pelvis is confined to elderly patients {971. hibernoma. It is extraordinarily rare and often found incidentally. Benign tumours Fibroepithelial polyps are exophytic intraluminal masses of vascular connective tissue and varying amounts of inflammatory cells. fibrous histiocytoma. 1456. Miscellaneous tumours Neuroendocrine tumours Villous adenoma and squamous papilloma These benign tumours are rare in the upper urinary tract. in contrast to urethral polyps.1347}. These aggressive tumours usually contain foci of urothelial carcinoma {971. including Benign epithelial tumours Urothelial papilloma and inverted papilloma Urothelial papilloma is usually a small.1326} and have a typical neuroendocrine immunohistochemical profile {971. The tumours may be associated with urothelial carcinoma in situ {2727. although it is the next most common tumour after urothelial carcinoma.1834}. The presence of a villous adenoma histology in a limited biopsy does not entirely exclude the possibility of adenocarcinoma.1321. Most adenocarcinomas are high grade and are widely invasive at presentation {590}. children are rarely affected {2828}.1217.1745.2884}. and periureteric lipoma.2634}. fibrosarcoma. Malignant tumours The most frequent malignant stromal tumour of the ureter is leiomyosarcoma. Lymphoma Renal pelvic and ureteric lymphomas are usually associated with systemic disease {200.331. Other malignant tumours reported are rhabdomyosarcoma.974. Pelvic and ureteric carcinoid is similarly rare {45.800.2635}.1347}. Most lesions are incidentally discovered.2712. and Ewing sarcoma {416. Survival for patients with pT3 and pT4 tumours.774. nephrolithiasis and repeated infections are predisposing factors. Carcinoids also occur in ureteroileal conduits {1343}.2882}. and presence and severity of concurrent urothelial neoplasia {163. it is very rare in both locations. mucinous or signet-ring cell phenotypes. core lined by normal urothelium. neurofibroma. malignant schwannoma. angiosarcoma. haemangioma. have been reported {91.774. Adenocarcinoma Pure adenocarcinomas of the renal pelvis and ureters are rare and enteric.1925.2882} and have a poor prognosis {621. and complete excision is essential.2260} and must be differentiated from metastatic disease {231}. Pure squamous cell carcinomas are usually high grade and high stage tumours and frequently invade the kidney. tumours with positive nodal disease and residual tumour after surgery is poor {1995}.2882}. delicate proliferation with a fibrovascular Tumours of the renal pelvis and ureter 153 .2870}.2573. Inverted papilloma is also rare being twice as common in the ureter as in the renal pelvis.and patients with pT2 tumours have a survival rate of 75% {1003. Survival for 5 years is rare {248}.657. Other prognostic factors include patient age. Glandular (intestinal) metaplasia. 506. type of treatment.1326. These tumours may occur in the background of nephrolithiasis with squamous metaplasia. Wilms tumour confined to the renal pelvis or extending into the ureter {1114} and cases of malignant melanoma and choriocarcinoma of the renal pelvis have been described {669.2680}. These are most frequently seen in the proximal ureter in young male adults and.2449.

Columnar and mucinous adenocarcinoma are thought to arise A B Fig.Tumours of the urethra F. Etiology Human papilloma virus plays a crucial role in the etiology of condyloma of the urethra. of Urology. A Transurethral endoscopic view of a non-invasive warty carcinoma of the Fossa navicularis urethrae (pTa). contribute to female preponderance of carcinomas. Peter Schneede.2318}. Villous adenoma has been shown to occur associated with tubulovillous adenoma and adenocarcinoma of the rectum {1782}. Molecular pathology Squamous cell carcinoma of the urethra is associated with HPV infection in female and male patients. Courtesy Dr. High risk HPV 16 or 18 was detected in 60 % of urethral carcinomas in women {2822}. B Transurethral endoscopic view of an invasive squamous cell carcinoma of the distal urethra (pT1) (Fossa navicularis). Leiomyoma may occur as a part of diffuse leiomyomatosis syndrome (esophageal and rectal leiomyomata). Leiomyoma may show expression of estrogen receptors and is related to endocrine growth stimulation during preg- nancy {72}. from glandular metaplasia. Dept. as they are three to four times more common in women than in men {85. when encountered. Peter Schneede. LMU Munich. Delahunt A.98 A. are usually malignant and perhaps unique among genitourinary malignancies. 2. 1799. The dissimilarities may chiefly be attributable to the distinct differences in the anatomy and histology of the urethra in the two sexes. Urethral carcinomas occurring in men are strikingly different in clinical and pathologic features when compared to tumours in women. of Urology. LMU Munich. Benign epithelial tumours are exquisitely rare in the urethra of either sex. frequently associated with chronic HPV infection.B. Hartmann Definition Epithelial and non-epithelial neoplasms of the male and female urethra. Dept. Congenital diverticulum as well as acquired strictures of the female urethra. . Amin B. B Non-invasive verrucous squamous cell carcinoma of the urethra with HPV infection and numerous koilocytes. A 154 Tumours of the urinary system B Fig.97 Urethra. whereas cribriform adenocarcinoma showed positive PSA staining indicating origin from prostate (male or female) {1837}. Courtesy Dr.920. Introduction and epidemiology Epithelial tumours of the urethra are distinctly rare but. 2. Hofstädter M.

clear cell or plasmacytoid). sheets or cords of cells accompanied by a desmoplastic and/or inflammatory response. clear cell adenocarcinoma (approximately 40%) and non-clear cell adenocarcinoma (approximately 60%). Female – Tumours of anterior urethra – Tumours of posterior urethra – Tumours of "paraurethral tissue" presenting as a urethral mass – Skenes glands Male – Tumours of penile urethra – Tumours of bulbomembranous urethra – Tumours of prostatic urethra – Tumours of "paraurethral tissue" presenting as a urethral mass – Prostate – Littres glands – Cowpers glands dence for an association of urothelial carcinoma with HPV. Tumours involving the distal urethra and meatus are most common and appear as exophytic nodular. Clear cell carcinomas are usually characterized by pattern heterogeneity within the same neoplasm and show solid. both in the urethra and the urinary bladder. CIS may involve suburethral glands. low grade and high grade carcinomas). Hamburg. and are characterized by irregular nests. erythema and ulceration (carcinoma in situ). but not at chromosomes 9 and 17 {732}.2532}. the latter frequently exhibiting myriad patterns that often coexist . Squamous cell carcinomas of the urethra span the range from well differentiated (including the rare verrucous carcinoma histology) to moderately differentiated (most common) to poorly differentiated.1955}.7. gelatinous or cystic consistency. Detection and typing of HPV with PCR and RFLP.3.2662}. Tumour staging There is a separate TNM staging system for tumours of the urethra {944. There is no convincing evi- Fig. Distal urethral and meatus tumours are squamous cell carcinomas (70%).99 Urethra. papillary (neoplasms of low malignant potential.4. The glandular differentiation may be broadly in the form of two patterns. ulcerative or infiltrative (carcinoma with and without invasion).2821}. They are identical to primary bladder adenocarcinomas. The cytoTumours of the urethra 155 In men. mucinous. Invasive carcinomas are usually high grade. and tumours of the proximal urethra are urothelial carcinomas (20%) or adenocarcinomas (10%) {85.8. signetring cell or adenocarcinoma NOS {640. courtesy Dr. micropapillary. unusual morphology (nested. microcystic. 2.20 and Y.Table 2. approximately 30% of squamous cell carcinomas tested positive for HPV16 {529.enteric. One squamous cell carcinoma of the urethra was investigated cytogenetically and showed a complex karyotype with alterations at chromosomes 2. IPM.11.6. tubular. Th. Tumours involving the proximal urethra that are urothelial in differentiation exhibit the macroscopic diversity of bladder neoplasia: papillary excrescences (non-invasive tumour). Carcinomas may occur within preexisting diverticuli. or rarely be accompanied by an undifferentiated component (small cell or sarcomatoid carcinoma).07 Anatomic classification of epithelial tumours of the urethra. HPV 16 in squamous cell carcinoma of the urethra. All tumours were located in the pendulous part of the urethra whereas tumours in the bulbar urethra were negative. . Epithelial tumours of the urethra Female urethra Malignant tumours Macroscopy Tumours may develop anywhere from urinary bladder to external vaginal orifice including accessory glands (Cowper and Littre glands as well as Skene glands in the female). Tumours may exhibit variable aberrant differentiation (squamous or glandular differentiation). infiltrative or papillary lesions with frequent ulceration. nodular. Adenocarcinomas are often large infiltrative or expansile neoplasms with a variable surface exophytic component and mucinous. Meyer. Urothelial neoplasms may be non-invasive. 1700. with or without papillary component. Histopathology The histopathology of female urethral carcinomas corresponds to the location. tubulocystic or papillary patterns. and papillary. focally or extensively mimicking invasion. carcinoma in situ (CIS) or invasive. HPV16-positive tumours had a more favourable prognosis {2821}.

proximal tumours have better overall survival than distal tumours (51% for proximal versus 6% for distal). high pT tumour stage and the presence of lymph node metastasis are adverse prognostic parameters {543. or cystic (adenocarcinoma). Fig. Squamous cell carcinomas are similar in histology to invasive squamous cell carcinomas at other sites. Tumour stage and location are important prognostic factors. papillary. Adenocarcinomas and squamous cell carcinomas are usually graded as per convention for similar carcinomas in other organs . Urothelial carcinoma may involve the prostatic urethra. Benign tumours Tumours occurring in males are similar to those described in the female urethra.100 Clear cell adenocarcinoma of urethra.2890}. A separate subsection deals with urothelial carcinoma of the prostate and prostatic urethra {944. In both sexes. 1487}. Tumour staging There is a separate TNM staging system for tumours of the urethra. alone or in combination. all being rare. cauliflower-like. The latter also includes inverted papilloma. exhibiting the same grade and histologic spectrum described in the female urethra. The histologic features are identical to neoplasms described in the urinary bladder and other sites.2905}. or entire tumours in females {920. 2. Grading of male and female urethral cancers Urothelial neoplasms are graded as outlined in the chapter on the urinary bladder. Prognostic and predictive factors The overall prognosis is relatively poor. Adenocarcinomas of the male urethra Male urethra Malignant tumours Macroscopy Tumours may occur in the penile urethra. sinus or fistulous Fibroepithelial and prostatic polyps Fibroepithelial polyps occur in both adults and children and are more common in the proximal urethra in males and the distal urethra in females {485. Features unique to prostatic urethral urothelial cancers are the frequent proclivity of high grade tumours to extend into the prostatic ducts and acini in a pagetoid fashion {2662. moderately. These tumours may arise in a urethral diverticulum or. Benign tumours Squamous papilloma. ill defined or reflective of histologic appearance – greyish-white or pearly with necrosis (squamous cell carcinoma) or mucoid. Histopathology Approximately 75% of carcinomas are squamous cell carcinoma (usually penile and bulbomembranous urethra). villous adenoma and urothelial papilloma of the urethra are the only three benign epithelial neoplasms.1700}. Prostatic polyps may cause hematuria but do not recur following resection. complication may be evident. Necrosis.usually show enteric. Differential diagnosis Nephrogenic adenoma Nephrogenic adenoma of the urethra is similar to that found elsewhere in the urinary tract.565}. Relationship to nephrogenic adenoma is controversial {85}. the remainder are urothelial carcinomas (usually prostatic urethra and less commonly bulbomembranous and penile urethra) or adenocarcinomas (usually bulbomembranous urethra) or undifferentiated {2905}. location often determines the gross appearance and the histopathology. Clear cell adenocarcinoma is distinctly rare {640}.2662}. The prognosis for clear cell adenocarcinoma may not be as unfavourable as initially proposed {543. In both sexes.2154.1736}. This tumour demonstrates a papillary architecture in which cells have clear cytoplasm and a high nuclear grade. Tumour appearance may be ulcerative. rarely.865. bulbomembranous urethra or the prostatic urethra. logic features vary from low grade and banal (resembling nephrogenic adenoma superficially) to high grade (more frequently).well. In situ lesions may be erythematous erosions (urothelial CIS) or white and plaque-like (squamous CIS). mitotic activity and extensive infiltrative growth are commonly observed. Abscess. In females and males. gelatinous. These polyps are covered by urothelial and/or prostatic epithelium and have a 156 Tumours of the urinary system . nodular. in association with mullerianosis {1954}. It may be synchronous or metachronous to bladder neoplasia. and 50% for proximal and 20% 5year survival for distal tumours in males {1118.2155}. colloid or signetring cell histology. and poorly differentiated carcinomas using the well established criteria of degree of differentiation. In females it is more frequently associated with urethral diverticulum and has also been noted after urethral reconstruction of hypospadia using bladder mucosa {2801.

papillary. Amelanotic melanoma may mimic urethral carcinoma {2130}. rarely.795}.2549.2770}. Haemangioma occurs in the bulbar {2020} or prostatic urethra {825}. female urethra. adenoid cystic. Other reported non-epithelial tumours are primary non-Hodgkin lymphoma {127.1325} and sarcomatoid carcinoma {1352. Leiomyoma is more frequent in Tumours of the urethra 157 . while rare mucinous and papillary adenocarcinomas of the paraurethral glands have been reported {301. but has been described also in the male {1740}. prostatic.1292.2160}. In male.1557.prominent basal epithelial cell layer {2453.2903}. mucinous or. Caruncles are inflammatory polyps of the female urethra and must be distinguished from exophytic inflammatory pseudotumour. Lymphoma or sarcomatoid carcinoma has to be differentiated from atypical stromal cells described in urethral caruncles with pseudoneoplastic histology {2897}.2414. desmin and actin {72}. Female periurethral gland adenocarcinomas are clear cell. Tumours of accessory glands Bulbourethral gland carcinomas may show a mucinous. Condyloma acuminatum and caruncle Urethral condylomas are flat or polypoid and are not always associated with external genital disease {583. acinar or tubular architecture. thra. the distal urethra is the most common site. Localized plasmacytoma has been shown to be treated by excisional biopsy {1473}. urothelial carcinoma or metastatic tumour {127. Benign tumours Non-epithelial tumours of the urethra Malignant tumours Malignant melanoma has been described in the male and female ure- Leiomyoma shows immunohistochemically positive staining for vimentin. 2440}. {2466}. Periurethral leiomyoma has been described associated with esophageal and rectal leiomyomatosis {969}.

partly due to the higher life expectancy.CHAPTER 3 X Tumours of of the Xxx Tumours the Prostate Prostate cancer contributes significantly to the overall cancer Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx burden. being the most frequent malignant neoplasia in men. The number of cases has continuously increased over the past decades. followed by Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx white people. while Asian people have the lowest risk. xxxxxxxx. Epidemiological data indicates that black people are most succeptable. . is currently being evaluated. Histopathological diagnosis and grading play a major role in the management of prostate cancer. caloric diet and lack of physical exercise. xxxxxxxx. An additionXxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx al factor is the Western lifestyle. characterized by a highly xxxxxxxx. The extent to which prostate cancer mortality can be reduced by PSA screening.

WHO histological classification of tumours of the prostate Epithelial tumours Glandular neoplasms Adenocarcinoma (acinar) Atrophic Pseudohyperplastic Foamy Colloid Signet ring Oncocytic Lymphoepithelioma-like Carcinoma with spindle cell differentiation (carcinosarcoma. Behaviour is coded /0 for benign tumours.org). and /1 for borderline or uncertain behaviour. 160 Tumours of the prostate . sarcomatoid carcinoma) Prostatic intraepithelial neoplasia (PIN) Prostatic intraepithelial neoplasia. grade III (PIN III) Ductal adenocarcinoma Cribriform Papillary Solid Haemangioma Chondroma Leiomyoma Granular cell tumour Haemangiopericytoma Solitary fibrous tumour Hematolymphoid tumours Lymphoma Leukaemia Miscellaneous tumours Cystadenoma Nephroblastoma (Wilms tumour) Rhabdoid tumour Germ cell tumours Yolk sac tumour Seminoma Embryonal carcinoma & teratoma Choriocarcinoma Clear cell adenocarcinoma Melanoma Metastatic tumours 9120/0 9220/0 8890/0 9580/0 9150/1 8815/0 8140/31 8480/3 8490/3 8290/3 8082/3 8572/3 8148/2 8500/3 8201/3 8260/3 8230/3 8440/0 8960/3 8963/3 9071/3 9061/3 9081/3 9100/3 0/3 8720/3 Urothelial tumours Urothelial carcinoma Squamous tumours Adenosquamous carcinoma Squamous cell carcinoma Basal cell tumours Basal cell adenoma Basal cell carcinoma Neuroendocrine tumours Endocrine differentiation within adenocarcinoma Carcinoid tumour Small cell carcinoma Paraganglioma Neuroblastoma Prostatic stromal tumours Stromal tumour of uncertain malignant potential Stromal sarcoma Mesenchymal tumours Leiomyosarcoma Rhabdomyosarcoma Chondrosarcoma Angiosarcoma Malignant fibrous histiocytoma Malignant peripheral nerve sheath tumour 8120/3 8560/3 8070/3 Tumours of the seminal vesicles Epithelial tumours Adenocarcinoma Cystadenoma Mixed epithelial and stromal tumours Malignant Benign Mesenchymal tumours Leiomyosarcoma Angiosarcoma Liposarcoma Malignant fibrous histiocytoma Solitary fibrous tumour Haemangiopericytoma Leiomyoma Miscellaneous tumours Choriocarcinoma Male adnexal tumour of probable Wolffian origin Metastatic tumours 8147/0 8147/3 8140/3 8440/0 8574/3 8240/3 8041/3 8680/1 9500/3 8935/1 8935/3 8890/3 9120/3 8850/3 8830/3 8815/0 9150/1 8890/0 8890/3 8900/3 9220/3 9120/3 8830/3 9540/3 9100/3 __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {808} and the Systematized Nomenclature of Medicine (http://snomed. /2 for in situ carcinomas and grade III intraepithelial neoplasia. /3 for malignant tumours.

N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Note: Metastasis no larger than 0. c T1. 4. but as T2. because of elevated PSA) T2 Tumour confined within prostate1 T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe. but not palpable or visible by imaging.2cm can be designated pN1mi M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) G Histopathological grading GX Grade cannot be assessed G1 Well differentiated (Gleason 2-4) G2 Moderately differentiated (Gleason 5-6) G3–4 Poorly differentiated/undifferentiated (Gleason 7-10) Stage grouping Stage I Stage II Stage III Stage IV T1a T1a T1b. Tumour found in one or both lobes by needle biopsy. T2 T3 T4 Any T Any T N0 N0 N0 N0 N0 N0 N1 Any N M0 M0 M0 M0 M0 M0 M0 M1 G1 G2. levator muscles.uicc. There is no pT1 category because there is insufficient tissue to assess the highest pT category.g. 3. 3–4 Any G Any G Any G Any G Any G Any G __________ 1 {944.2662}. or pelvic wall4 Notes: 1. rectum. 2 A help desk for specific questions about the TNM classification is available at http://www. but not both lobes T2c Tumour involves both lobes T3 Tumour extends beyond the prostate2 T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) T4 Tumour is fixed or invades adjacent structures other than sem inal vesicles: bladder neck.TNM classification of carcinomas of the prostate T – Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Clinically inapparent tumour not palpable or visible by imaging T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e..org/tnm/ 161 . Invasion into the prostatic apex yet not beyond the prostate is not classified as T3. 2. external sphincter. is classified as T1c. Microscopic bladder neck involvement at radical prostatectomy should be classified as T3a.

M. Lopez-Beltran R.4–2. Helpap P. all ages. Similarly. the risk of prostate cancer in Black males was 1.Acinar adenocarcinoma J. survival is significantly greater in high-incidence countries (80% in the USA vs. in 2000.6% of cancer deaths in men. Iczkowski A.01 Mortality from prostate cancer. Allsbrook Jr.A.g. and mortality is significantly higher also among migrants from the Caribbean (RR 1. Furusato U. who in turn have rates considerably higher than populations of Asian origin (e. and lower in the East and South. This represents 9. but tend to be higher in the countries of northern and western Europe. and the prevalence greatly exceeds the cumulative incidence in the same population.3 % in developed countries and 4. Mortality rates are low in Asian populations. and in much of sub-Saharan Africa.S. Montironi M. However.A is 26 fold (while it is almost 90 fold for incidence). and in North Africa. some 70% higher than in Whites. Migrants Migrants from West Africa to England & Wales have mortality rates 3. Egevad M.8 (95% CI 1. These international differences are clearly reflected within the United States. for example.3) times that of White men {297}.000 deaths (5. Thus. making this the most prevalent form of cancer in men. Brazil. 3. Mortality is less affected by the effects of early diagnosis of asymptomatic cancers. with 201. this more favourable prognosis could well be due to more latent cancer being detected by screening procedures {310}.M. Algaba W. Two international studies of latent prostate cancer {316. Hamper B. or at autopsy. Bastacky L. The difference in mortality between China and the U.000 in the year 2000. Incidence rates in Europe are quite variable. 3. The estimated number of cases was 513. parts of South America (Brazil) and the Caribbean. 162 Tumours of the prostate . Sakr H. incidence rates reflect not only differences in risk of the disease.4–5.A. Chinese. world standard population. and by detection of latent cancer in tissue removed during prostatectomy operations. recorded 'incidence' may be very high (in the United States. and third in importance in men {2012}. ICD-O code 8140/3 Epidemiology Geographical distribution Prostate cancer is now the sixth most common cancer in the world (in terms of number of new cases). Latent cancers are frequent in older men. where the Black population has the highest incidence (and mortality) rates. 95% CI 1.2874} observed that prevalence increases steeply with age. From Globocan 2000 {749}.0). Whites.5 times (95% CI 2.I. In recent years. Mortality rates are high in North America. Parkin Definition An invasive malignant epithelial tumour consisting of secretory cells.A. Age adjusted rates (ASR).A.5–2. Epstein F. The frequency of latent carcinoma of prostate in Japan is increasing (as with clinical prostate cancer) and may eventually approach the prevalence for U.5 million at 5 years.3% in developing countries). It is a less prominent cause of death from cancer. but depends upon survival as well as incidence. Prostate cancer remains relatively rare in Asian populations. The low fatality means that many men are alive following a diagnosis of prostate cancer – an estimated 1. where it is now by far the most commonly diagnosed cancer in men). Incidence is very high also in Australia and the Scandinavian countries (probably also due to screening). but also the extent of diagnosis of latent cancers both by screening of asymptomatic individuals.7. but varies much less between populations than the incidence of clinical cancer. especially where screening is widespread. Humphrey K. The country/ethnic-specific ranking was much the same.7% of cancers in men (15.2% of all cancer deaths). 40% in developing countries). S. Rubin W.S.M. Japanese and Korean males).1) those of the local-born population. North and West Europe.C. Samaratunga D. De Marzo L. Boccon-Gibod A. Australia/New Zealand. in São Paulo. in Fig.

even in Japanese born in the United States. Parkin et al. Localized prostate cancer forms a small proportion of cases in Japan (24%) compared with 66-70% in the U.03 Prostate cancer incidence: ASR (World) per 10 5 (1993-1997). White populations. Fig. In the USA. Migrants from low-risk countries to areas of higher risk show quite marked increases in incidence (for example. which suggests that genetic factors are responsible for at least some of the differences between ethnic groups. {1130}. all transurethral prostatectomy (TURP) sections were carefully examined {2392}. especially in younger men.02 International trends in age-standardized mortality rates of prostate cancer (world standard). about three-quarters of all cases occur in men aged 65 or more. Source: WHO/NCHS Age distribution The risk of prostate cancer rises very steeply with age. The largest increases in incidence. 3. rates in Japanese migrants remain well below those in the U. there was also an increase in the rate of increase in mortality.S. Acinar adenocarcinoma 163 . Some of this change reflects an elimination of the 'diagnostic bias" influencing the international incidence rates. The increased mortality was probably partly due to mis-certification of cause of death among the large number of men who had been diagnosed with latent prostate cancer in the late 80’s and early 90’s. prostate cancer incidence rates were increasing slowly up to the 1980’s. probably due to a genuine increase in risk. and accelerating after 1988. for example. mortality among migrants from East Africa. Incidence of clinical disease is low until after age 50. there was a rapid increase in incidence. coupled with increasing diagnosis of latent. {2016}. Time trends Time trends in prostate cancer incidence and mortality have been greatly affected by the advent of screening for raised levels of serum Prostate-Specific Antigen (PSA). due to the increasing use of TURP {2099}. More recently. With the introduction of PSA screening. with the increase being mainly in younger men (under 65) and confined to localized and regional disease. probably because most of the prevalent latent cancers in the subset of the population reached by screening had already been detected {1467}. it seems unlikely that screening was entirely responsible. compared with the 5-6th power for other epithelial cancers {488}.A. are not high {966}. (since 1992 in White men. mortality rates have decreased. and in incidence and mortality by Hsing et al. Fig. 3. but this was very much less marked than the change in incidence. {1956}. Beginning in 1986.1015}. 1 From D. asymptomatic cancers in prostatectomy specimens. The later decline may be partly due to a reversal of this effect. However. The contribution that PSA screening and/or improved treatment has made to this decline has been the subject of considerable debate {728. incidence in Japan could be 3-4 times that actually recorded if. International trends in mortality have been reviewed by Oliver et al.contrast. allowing increasing detection of preclinical (asymptomatic) disease {2100}. The incidence rates began to fall again in 1992 (1993 in Black males). Japanese living in the United States). The recorded incidence of prostate cancer doubled between 1984 and 1992. Worldwide.M. and then increases at approximately the 9-10th power of age. of predominantly Asian (Indian) ethnicity. 1994 in Black men). 763.S.

The evidence from these studies for a protective effect of fruits and vegetables on prostate cancer. B Computerized reconstruction of prostatectomy specimen with typical. There may be a contribution from improvements in treatment which is difficult to evaluate from survival data because of lead-time bias introduced by earlier diagnosis. although few studies have adjusted the results for caloric intake. Some of this increase may be due to greater awareness of the disease. the changes in rates with time. In a few cases. A similar study involving a population-based case–control study of prostate cancer among Blacks. and findings of elevated risk in men with a family history of the disease support this.5 x in Shanghai. Genetic factors appear therefore to play a major role in explaining the observed racial differences. but more interest is focused on the AR gene. It is clear that male sex hormones play an important role in the development and growth of prostate cancers. multifocal distribution of cancer. There is a 5-11 fold increased risk among men with two or more affected first-degree relatives {2499}. especially red meat. There is a strong positive association with intake of animal products. 164 Tumours of the prostate . Etiology The marked differences in risk by ethnicity suggest that genetic factors are responsible for at least some of the differences between ethnic groups. China. Despite extensive research. But it is also probable that there is a genuine increase in risk occurring. which has been postulated to partly explain their susceptibility to prostate cancer {2091. But there have been large increases also in low risk countries. 2. Multifocal adenocarcinoma of the prostate is present in more than 85% of prostates {354}. Australia). but do not seem to play a clear role. A cohort study of health professionals in the United States. in several high-risk populations. or for a link with obesity {1348. Testosterone diffuses into the gland. rather more marked in older than in younger men.2842}. UK) {1956}. there have been declines in mortality from prostate cancer since around 19881991. probably partly the effect of increasing detection following TURP. As in the USA. Blacks in the United States have fewer CAG repeats than Whites.have been seen in high-risk countries. the normal range being 6–39 repeats. between 1975 and 1995 {2016. Japan.2246}. 1.2788}. Polymorphisms in the SRD5A2 genes may provide at least part of the explanation {2389}. located on the long arm of chromosome X.81) of prostate cancer in Blacks versus Whites {2091}. Other genetic mechanisms possible related to prostate cancer risk are polymorphisms in the vitamin D receptor gene {1169. Nevertheless. Whites and Asians in the United States and Canada found the prevalence of positive family histories somewhat lower among the Asian Americans than among Blacks or Whites {2815}. including those controlling cell division. due to use of PSA. but this is not the case in others where the falls in mortality are just as marked (France. although 15-25% have tumour predominantly within the transition zone {716}. but there is no evidence for significant interethnic differences in these systems. 3. case–control and cohort studies implicates dietary fat in the etiology of prostate cancer. Germany.6 x in Miyagi. and diagnosis of small and latent cancers. yet cancers uncommonly arise in this zone. Several studies suggest that men with a lower number of AR CAG repeat lengths are at higher risk of prostate cancer {404}. Evidence from ecological.7 x in Hong Kong. and. large transition zone tumours may extend into the peripheral zone and become palpable. Only in India (Bombay) does there seem to have been little change (+13%) in incidence. Nonpalpable cancers detected on needle biopsy are predominantly located peripherally. Large tumours may extend into the central zone. There is little evidence for anthropometric associations with prostate cancer. but quite substantial nevertheless (15-25%).0 x in Singapore Chinese. more recently. Localization Most clinically palpable prostate cancers diagnosed on needle biopsy are predominantly located posteriorly and posterolaterally {354. A B Fig. DHT and testosterone bind to the androgen receptor (AR). Italy. and on migration. the environmental risk factors for prostate cancer are not well understood. Much research has concentrated on the role of polymorphisms of the genes regulating this process and how inter-ethnic variations in such polymorphisms might explain the higher risk of prostate cancer in men of African descent {2246}. the increase in mortality rates is large. 3. The increases in rates in the "high risk" countries were much less than for incidence. The AR gene contains a highly polymorphic region of CAG repeats in exon 1. also imply that differences in environment or lifestyle are also important. 3. Other environmental factors (occupational exposures) or behavioural factors (sexual life) have been investigated. is not convincing. and not much inferior to the changes observed in incidence.1170} or in the insulin-like growth factor (IGF) signalling pathway {403}. there has been considerable screening activity. This is confirmed by studying changes in mortality. and no particular fat component has been consistently implicated. In some of the countries concerned (Canada. In low risk countries. where it is converted by the enzyme steroid 5-alpha reductase type II (SRD5A2) to the more metabolically active form dihydrotestosterone (DHT).04 A Low magnification of a section of radical prostatectomy showing the location of prostate cancer. found that differences in the distribution of possible dietary and lifestyle risk factors did not explain the higher risk (RR 1. Cancers detected on TURP are predominantly within the transition zone.1682}. unlike many other cancer sites. and the receptor/ligand complex translocates to the nucleus for DNA binding and transactivation of genes which have androgen-responsive elements.

06 Transrectal ultrasound of prostate shows the hypoechoic cancer is marked with 2 xs. Results from these studies are however conflicting due to a problematic overlap in flow detected in cancers. Enlarged lymph nodes. Its primary application. Newer colour flow techniques such as power Doppler US may be helpful as they may allow detection of slow flow in even smaller tumour vessels. Computed tomography and magnetic resonance imaging Cross-sectional imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have Acinar adenocarcinoma 165 . Clinical features Signs and symptoms Even before the serum prostate specific antigen test came into common usage over a decade ago. Sonographic-pathologic correlation studies have shown that approximately 70-75% of cancers are hypoechoic and 25-30% of cancers are isoechoic and blend with surrounding tissues {539.Fig. as well as delineate and measure focal lesions. A small number of cancers are echogenic or contain echogenic foci within hypoechoic lesions {1010}.658. However. remains in image guidance of transrectal prostate biopsies. because not all cancers are hypoechoic and not all hypoechoic lesions are malignant {1012}. usually pelvic. inflammatory conditions or benign lesions.1885. 3. where it can cause cord compression {1138}. Imaging Ultrasound imaging Transrectal ultrasound imaging (TRUS) with high frequency transducers is a useful tool for the work-up of patients with a prostate problem. To improve lesion detection the use of colour Doppler US (CDUS) has been advocated particularly for isoechoic lesions or to initiate a TRUS guided biopsy which may not have been performed.2196}. and rarely. 3.2195}. assess extraglandular spread or monitor patients with prostate cancer undergoing hormonal treatment {364. detected by digital rectal examination. However. can sometimes be a presenting symptom. Most cancers arise in the peripheral zone. B Radiography of prostate carcinoma metastatic to femur. A B Fig. A large multicentre study demonstrated that up to 40% of significant cancers were missed by TRUS. It enables the operator to evaluate gland volume. and hence further lowered the percentage of cancers that present with symptoms today. The positive predictive value of a hypoechoic lesion to be cancer increases with the size of the lesion. While the majority of early prostate cancers present as hypoechoic lesions in the peripheral zone on TRUS.05 A Gross photography of prostate carcinoma metastatic to femur (post fixation). Other recent developments such as intravenous contrast agents. These cancers cannot be detected by TRUS. a palpable abnormality in this region and an elevated PSA level {689}.2285}. however. Metastatic prostatic adenocarcinoma can present as bone pain. urinary obstruction results from large-volume periurethral tumour. most prostate cancer was asymptomatic. rectal bleeding or obstruction {2348}. harmonic imaging and 3-D US have shown a potential role for these US techniques to delineate subtle prostate cancers. but rarely supraclavicular or axillary (typically left-sided). Locally extensive cancer is seen less often than in the past but may present with pelvic pain. Even with high-resolution equipment many potentially clinically significant cancers are not visualized by TRUS.0% of contemporary transurethral resection specimens disclose carcinoma {1605}. Ascites and pleural effusion are rare initial presentations of prostate cancer. this sonographic appearance is non-specific. In addition. mainly in the pelvic bones and spinal cord. when bone scan discloses metastasis after diagnosis of a primary prostatic carcinoma. PSA screening has decreased the average tumour volume. so that transition zone enlargement sufficient to cause bladder outlet obstruction usually indicates hyperplasia. the metastasis is most often asymptomatic {2487}. Overall the incidence of malignancy in a sonographically suspicious lesion is approximately 20-25% {2193}.1013}. 8. It has proven to be of limited value for the detection of prostate cancer and the assessment of extraglandular spread due to lack of specificity. thus tailoring the biopsy to target isoechoic yet hypervascular areas of the gland {56. the sensitivity to detect neurovascular bundle invasion has been reported to only be about 66% with a specificity of 78% {1011.

conventional assays do not measure PSA-AMG. These result from complex formation between free PSA and two major extracellular protease inhibitors that are synthesized in the liver. 2149.2558}. with positive bone scintigraphy..08 Bone scanning showing multiple metastases of a prostate carcinoma. white men under age 50 have PSA values <2. In contrast.2185}. The PSA gene is located on chromosome 19 {2211. Based on the 95th percentile values in a regression model.1499. Macroscopic photograph. N. Only a small percentage of the PSA found in the serum is free. 3.1621}. MRI is sometimes reserved for staging of patients with biopsy proven prostate cancer {2605}. No PSA epitopes that interact with anti-PSA antibodies are exposed on the PSA-AMG complex. zymogen) for PSA or an inactive nicked or damaged form of the native molecule. Different molecular forms of PSA exist in serum {392. Subfractions of free PSA include: mature single-chain. It has been suggested that these age-related values be used as the upper limit of normal in 166 Tumours of the prostate . a 67 kDa single chain glycoprotein.07 A Pelvic metastases of prostate carcinoma. This precursor. Plain film radiography and nuclear medicine Skeletal radiography (bone survey) is an insensitive method to screen for bony metastases and should be reserved to confirm skeletal abnormalities in patients Serum total PSA and age specific reference ranges Serum PSA is determined with immunoassay techniques. Laboratory tests Prostate specific antigen (PSA) PSA is produced by the epithelial cells lining the prostatic ducts and acini and is secreted directly into the prostatic ductal system. As PSA is a serine protease. under age 60 have PSA values <3. Cytogen Corporation.A B Fig.) has shown promise to detect microscopic metastatic deposits in regional and distant sites.1498. under age 70 have PSA values <4. Its andro- gen-regulated transcription results in the biosynthesis of a 261 amino acid PSA precursor.1937. Monoclonal antibodies have been designed to detect the free form of PSA (29kDa). a 720 kDa glycoprotein. Because this free form does not bind to ACT or AMG. Monoclonal antibody radioimmunoscintigraphy (prostate specific membrane antigen-PMSA) chelated to Indium111 (Prostacint®.2910}. 2594 . Another new development in the field of nuclear medicine is positron emission tomography (PET). prostase (hK4) or trypsin. These techniques however. also appear to have limitations for imaging of microscopic disease {1412. It has been found that total PSA correlates well with advancing age {92. such as tumour aggressiveness and extra-prostatic extension {2911}. it is thought to be either the enzymatically inactive precursor (i. prostin (hK15).g. due to limited positive predictive values reported (50-62%) its use in combination with PSA.2022. This is thought to result from the 25fold larger AMG molecule "engulfing" PSA and hindering recognition of PSA epitopes.5 ng/ml. and multichain. hK2.1667}. Upper urinary tract obstruction may also be identified on bone scintigraphy obviating the need for intravenous urography. its normal mode of existence in the serum is in a complex with α-1-anti-chymotrypsin (ACT). 2911}. histologic grade and clinical staging is recommended to provide increased predictive information {147. Knowledge obtained from MRSI may provide insight into the biological behaviour of prostate cancer. Conversion from inactive proPSA to active PSA requires action of exogenous prostatic proteases. 3. PSA-ACT can therefore be readily measured in serum {1498. which allows in vivo-characterization of tumours and may have implications for the evaluation of patients with prostate cancer in the future. nicked free PSA forms.2504}. C Radiography of the same case not proven valuable because of low sensitivities to detect and stage prostate cancer {1011. Therefore.J. and α-2-macroglobulin (AMG). e. Bone scintigraphy (radionuclide bone scans) provides the most sensitive method for detecting bone metastases. is believed to be activated by the proteolytic liberation of a small amino-terminal fragment {2098}. only one major PSA epitope is completely shielded by complex formation with ACT. 546.576. B Spinal osteoblastic metastases from prostate cancer. However. C Fig.5 ng/ml.e.5 ng/ml.483. the complex of PSA and ACT (90 kDa) and the total PSA. and under age 80 PSA levels were <6. The combined use of MRI and proton MRI-spectroscopy imaging (MRSI) is currently being evaluated for staging of prostate cancer. Princeton.5 ng/ml.

109. The median values of total PSA and of the free-to-total PSA ratio are 7.2847}. Serum PAP may be significantly elevated in patients with BPH. Human glandular kallikrein 2 (hK2) The gene for hK2 has a close sequence homology to the PSA gene. There is a significant difference in free-to-total PSA ratio between prostate cancer and BPH patients with prostate volumes smaller than 40 cm3. men with faster doubling time. However.4 ng/ml and 23. it seems logical that nodular hyperplasia volume rather than total volume should be used when trying to interpret elevated levels of serum PSA. Prostate markers other than PSA Prostatic acid phosphatase (PAP) PAP is produced by the epithelial cells lining the prostatic ducts and acini and is secreted directly into the prostatic ductal system. PSA tests are also useful to detect recurrence and response of cancer following therapy.C5. The exact value used to define recurrence varies depending on the treatment modality. hK2 and PSA exhibit different proteolytic specificities.5% in prostate cancer patients.381}. according to studies with monoclonal antibody 7E11.5 years (median. as well as in a complex with ACT {2074}. PSA density of the transition zone (PSA TZD) is more accurate in predicting prostate cancer than PSA density for PSA levels of less than 10 ng/ml {625}. equal to serum PSA divided by prostate epithelial volume as determined morphometrically in biopsies) should be superior to PSAD. Prostate cancer may also be present in men with serum PSA values lower than the above quoted cutoff points. and in the United States African American men). However.5-6. PSA is elevated beyond the arbitrary cutoff point of 4. are obviated by assays for complex PSA.3 ng/ml and 20. Therefore.050 ng/ml/cm3). serum PSA lacks high sensitivity and specificity for prostate cancer.. PSAD). 4. The free form of PSA occurs to a greater proportion in men without cancer {2607} and. Complex PSA value may offer better specificity than total and free-tototal PSA ratio {308}.6 years (median. particularly assay variability. which can be measured by transrectal ultrasound (total PSA/prostatic volume = PSA density. PAP was the first serum marker for prostate cancer. the doubling time for Free PSA. PSA doubling time (PSA DT) is closely related to PSA velocity {1470}.0 ng/ml in the majority of patients with prostate cancer. studies of the Acinar adenocarcinoma 167 PSA density of the transition zone. and 1. especially in men with diagnosed prostate cancer and not proportional to total PSA or free PSA concentrations. Problems associated with the free-to-total PSA ratio. Prostate specific membrane antigen (PSMA) Although it is not a secretory protein. Therefore.051 to 0.1 ng/ml/cm3). Given the shortterm variability of serum PSA values.1521}. The prostate-specific antigen epithelial density (PSAED. It may also be greater than 4.2412. Therefore. PSMA is a membrane-bound glycoprotein with high specificity for benign or malignant prostatic epithelial cells {142. but not between patients in these two groups with prostate volumes exceeding 40 cm3 {2506}. by contrast. patients with local/regional and advanced/metastatic disease ranges from 1. Prostate-specific antigen epithelial density. Serum PAP currently plays a limited role in the diagnosis and management of prostate cancer. The production of PSA per volume of prostatic tissue is related to the presence of BPH and prostate cancer and to the proportion of epithelial cells and the histological grade of the carcinoma {1476}. including benign prostatic hyperplasia (BPH). 1125. PSA change has both a linear and exponential phase. This problem has been partially overcome by calculating several PSA-related indices and/or evaluating other serum markers {1660. respectively {1470. family history. hK2 is found to form a covalent complex with ACT at rates comparable to PSA. This may be specifically true for men considered at higher risk (i. During the exponential phase. presence of inflammation. vascularity. 2941}.099 ng/ml/cm3) and pathological (equal to or greater than 0. and the increased magnitude of error when the quotient is derived.6% in a control group of men without BPH {2506}. intermediate (from 0. It has been demonstrated that the rate of increase over time is greater in men who have carcinoma as compared to those who do not {380. Patients with BPH have PSA doubling times of 12 ± 5 and 17 ± 5 years at years 60 and 85.8 ng/ml and 10.2846. PSA velocity and PSA doubling time PSA velocity (or PSA slope) refers to the rate of change in total PSA levels over time. and other unrecognized phenomena {2698.0 ng/ml in some benign conditions. An elevated concentration is associated with the presence of prostate cancer.1842. the α-1chymotrypsin complex PSA comprises a greater proportion of the total PSA in men with malignancy.1839. The sensitivity and specificity of this tumour marker are far too low for it to be used as a screening test for prostate cancer {1660}. This is linked to the fact that the doubling time of prostate cancer is estimated to be 100 times faster than BPH. hK2 messenger RNA is localized predominately to the prostate in the same manner as PSA. The serum level of hK2 is relatively high. This is a novel prognostic marker that is present in the serum of healthy men. The PSAD values are divided into three categories: normal . PSMA levels correlate best with advanced stage. 2 years).9-8. serum PSA velocity should be calculated over an 18-month period with at least three measurements.1775}. 3 years) and 0. prostatitis. but show similar patterns of complex formation with serum protease inhibitors. In patients with prostate cancer.1775}. This difference in serum expression between hK2 and PSA allows additional clinical information to be derived from the measurement of hK2. serum hK2 is detected in its free form. (values equal or lower than 0. prostatic infarction or prostate cancer.e. The serum PSA level is most strongly correlated with the volume of epithelium in the transition zone. Nodular hyperplasia is the main determinant of serum PSA levels in patients with BPH {139. PSA density This is the ratio of the serum PSA concentration to the volume of the gland.8% in patients with BPH. Complex PSA. respectively. In particular. or with a hormonerefractory state.PSA-related diagnostic strategies. the amount of PSA produced by individual epithelial cells is variable and serum levels of PSA may be related to additional factors such as hormonal milieu.

This cannot be performed unless biopsies have been specifically designated as to their location. than 5% of the specimen it is stage T1a.2598}. Submission should be random to ensure that the percentage of the specimen area involved with cancer is representative for the entire specimen. A TURP specimen may contain more than a hundred grams of tissue and it is often necessary to select a limited amount of tissue for histological examination.724. The location and extent of cancer may be critical for the clinician when selecting treatment option {2151}.1838. Cancers detected at TURP are often transition zone tumours.2214}.8-4. there is the possibility that extremely low-level basal transcriptions of prostate-specific genes from non-prostate cells will result in a positive RT-PCR signal.2223}. sparing a repeat biopsy {939}. This increased yield relates to the addition of biopsies sampling the more lateral part of the peripheral zone. However. It has therefore been suggested that intervening unstained sections suitable for immunohistochemistry are retained in case immunohistochemistry would be necessary. The sextant protocol samples the apex. The most common fixative used for needle biopsies is formalin. FNA is still used in some countries and has some advantages. When atypia suspicious for cancer is found. which enhance nuclear details are also in use. Immunohistochemistry for high molecular weight cytokeratins provides considerable help in decreasing the number of inconclusive cases from 6-2% {1923}. The technique is cheap. usually relatively painless and has low risk of complications.3% of all cancers detected) and transition zone biopsies are usually not taken in the initial biopsy session {778. where a significant number of cancers are located. In young men. Most studies have found few additional cancers by adding transition zone biopsies to the sextant protocol (1. submission of the entire specimen may be considered to ensure detection of all T1a tumours. However. Directed biopsies to either lesions detected on digital rectal examination or on ultrasound should be combined with systematic biopsies taken according to a standardized protocol {1008. but in a minority there is substantial tumour located in the periphery of the prostate {711}.1703}.09 Needle biopsies sampling the lateral part of the peripheral zone (PZ) improve detection of prostate cancer (red). prostate cancer is incidentally detected in approximately 810% of the specimens.1685. Handling of TUR specimens. Submission of 8 cassettes will identify almost all stage T1b cancers and approximately 90% of stage T1a tumours {1847.1927}. the sensitivity of FNA was usually found to be comparable with that of core biopsies {2765}.expression of PSMA in serum of both normal individuals and prostate cancer patients using western blots have provided conflicting results in some laboratories {635. Methods of tissue diagnosis Needle biopsies The current standard method for detection of prostate cancer is by transrectal ultrasound-guided core biopsies. a repeat biopsy should concentrate on the initial atypical site in addition to sampling the rest of the prostate. More recently. hence. Approximately 15-22% of prostate cancers arise in the transition zone. but they may also be of peripheral zone origin. Reverse transcriptase-polymerase chain reaction RT-PCR is an extremely sensitive assay.1686}. they can be placed into the same block.8% of prostate biopsies. If the tumour occupies less Fine needle aspiration cytology Before the era of transrectal core biopsies. If two cores are taken from the same region.1841. However. Most men who undergo total prostatectomy for T1a cancer have no or minimal residual disease. Guidelines have been developed for whether additional sampling is needed following the initial detection of cancer in a TURP specimen {1673}. quick. Handling of needle biopsies. This high degree of sensitivity mandates that extreme precaution be taken to avoid both cross-sample and environmental contamination. Prostate biopsies from different regions of the gland should be identified separately. Fig. basal PSA mRNA levels were detected in a quantitative RT-PCR in individuals without prostate cancer. although alternative fixatives. 3. Several strategies for selection have been evaluated. Recent studies have shown that protocols with 10 to 13 systematic biopsies have a cancer detection rate up to 35% superior to the traditional sextant protocol {105. in the uncommon situation of less than 5% of cancer with Gleason score 7 or higher. particularly when they are large {941. prostate cancer was traditionally diagnosed by fine needle aspiration (FNA). In early studies comparing FNA and limited core biopsy protocols. and otherwise stage T1b. mid and base region bilaterally {1099}. Because of the high sensitivity of RT-PCR. Intervening slides are critical to establish a conclusive diagnosis in 2. while sextant biopsies mainly sample the peripheral zone. 2151}. capable of detecting one prostate cell diluted in 108 non-prostate cells. the use of FNA for diagnosing prostate cancer has disadvan- 168 Tumours of the prostate . blocking more than two biopsy specimens together increases the loss of tissue at sectioning {1272}. patients are treated as if they had stage T1b disease. Several modifications of the sextant protocol have been proposed. Transurethral resection of the prostate When transurethral resection of the prostate (TURP) is done without clinical suspicion of cancer. Sextant biopsies aim at the centre of each half of the prostate equidistant from the midline and the lateral edge while the most common location of prostate cancer is in the dorsolateral region of the prostate. It is recommended that the extent of tumour is reported as percentage of the total specimen area. thus suggesting the need to quantitate the RTPCR assay in order to control for basal transcription {2730}. The normal histology of the prostate and its adjacent structures differs between base and apex and knowledge about biopsy location is helpful for the pathologist. A potential problem with these alternative fixatives is that lesions such as high-grade prostatic intraepithelial neoplasia may be over-diagnosed. These problems with RT-PCR have limited its clinical utility {1780.

be confirmed by core biopsies. of higher grade and stage. Subtle tumours may be grossly recognized by structural asymmetry. Visceral metastatic deposits in the lung and liver are not often clinically apparent. and in advanced cases. Before treatment of localized prostate cancer. The TNM classification scheme {944. 1001. is based on the histological architecture of glands and cannot be applied on cytology. with an osteoblastic response.1685. The peripheral zone carcinomas often grow into periprostatic soft tissue by invading along nerves {2735} or by direct penetration out of the prostate. Extraprostatic invasion superiorly into the bladder neck can occur with larger tumours. including direct extension from carcinoma in adjacent soft tissue. this can lead to bladder neck and ureteral obstruction. and presciatic nodes. compared with grossly inapparent tumours (usually < 5 mm). prostatic intraepithelial neoplasia and contamination of seminal vesicle epithelium. Gross haemorrhage and necrosis are rare. C Section of prostate showing transition zone adenocarcinoma. However. tages.1001}. The bones most frequently infiltrated by metastatic disease are. solid. Tumour spread and staging Local extraprostatic extension typically occurs along the anterior aspect of the gland for transition zone carcinomas. and may not be evident grossly {701. the tumours contrast with the adjacent benign parenchyma. for example. Gleason grading. which is typically tan and spongy {289. ribs. Extension into the seminal vesicles can occur by several pathways. Denovillier’s fascia constitutes an effective physical barrier {2734}. and via lymphvascular space channels {1944}. periprostatic/ periseminal vesicle lymph nodes may be the first ones to harbour metastatic carcinoma. and are frequently palpable. therefore. C Fig. Posteriorly. In countries with widespread PSA testing. 3. pelvic bones.11 A Transition zone cancer with yellow nodule in the anterior right area. sacrum. is a hallmark of disseminated prostate cancer {835}. skull. In general. In a few patients. low grade and low stage {2168}.A B Fig. common iliac. femur.10 A. Histopathology Adenocarcinomas of the prostate range from well-differentiated gland forming cancers.1001. and humerus. but these nodes are found in less than 5% of radical prostatectomy specimens {1364}. cervical spine.701. grossly evident prostate cancer has become relatively uncommon. as there is no well-defined capsule surrounding the entire prostate this term is no longer recommended. Macroscopy On section. which are often nonpalpable. Metastatic spread of prostatic carcinoma begins when carcinoma invades into lymphvascular spaces. and peripherally may expand or obscure the outer boundaries of the prostate. Metastasis to bone marrow. Causes of gross false positive diagnoses include confluent glandular atrophy. The most common sites of metastatic spread of prostatic carcinoma are the regional lymph nodes and bones of the pelvis and axial skeleton. Potential sources of false positive diagnosis with FNA are inflammatory atypia. granulomatous prostatitis and infection {1001}. the diagnosis should. which is essential for the clinician. followed by external iliac. in descending order. microscopical extent of tumour. and range in colour from white-grey to yellow-orange.B Section of prostate showing peripheral zone adenocarcinoma. Core biopsies.290. spread along the ejaculatory duct complex. Anterior and apical tumours are difficult to grossly identify because of admixed stromal and nodular hyperplasia {289. B Transition zone cancer. presacral. The term "capsule" has been used to denote the outer boundary of the prostate. grossly evident cancers are firm. but are common in end-stage disease. and in posterolateral sites for the more common peripheral zone carcinomas {1684}. difficult to distinguish from nodules of BPH. where it is often difficult to disAcinar adenocarcinoma 169 . dorsal and lumbar spine. and direct prostatic carcinoma spread into the rectum is a rare event. healed infarcts. peripheral zone tumours may deform the periurethral fibromuscular concentric band demarcating the periurethral and peripheral prostate centrally. unlike FNA. Tumours usually extend microscopically beyond their macroscopic border. the latter having increased cytoplasmic lipid. 3. 2662} is the currently preferred system for clinical and pathologic staging of prostatic carcinoma. stromal hyperplasia.2905}. provide information about tumour extent and occasionally about extra-prostatic extension and seminal vesicle invasion. Some large tumours are diffusely infiltrative. small.2905}. The obturator and hypogastric nodes are usually the first ones to be involved. grossly recognizable tumours tend to be larger.

tinguish them from benign prostatic glands. and poorly formed glands. gland-forming prostate cancers typically contain glands that are more crowded than in benign prostatic tissue. Benign prostate glands. Conversely.12 A Organ-confined adenocarcinoma of the prostate extending to edge of gland. Glands of adenocarcinoma of the prostate typically grow in a haphazard fashion. nuclear. 3. 3. Tumours composed of solid sheets. Glands oriented perpendicular to each other and glands irregularly separated by bundles of smooth muscle are indicative of an infiltrative process. These cells when labeled with basal cell specific antibodies are negative and represent fibroblasts closely apposed to the neoplastic glands. basal cells may not be readily recognized in benign glands without the use of special studies. fused glands. the distinction between benign glands based on the architectural pattern becomes more apparent. cords of cells. although there is overlap with certain benign mimickers of prostate cancer. 3. and its distinction from benign glands. A B Fig. and intraluminal features. In cases of obvious carcinoma. or are evenly dispersed in the peripheral zone {1685}.15 Extraprostatic extension by prostatic adenocarcinoma. In contrast. These architectural patterns are key components to the grading of prostate cancer (see Gleason grading system). 170 Tumours of the prostate . A feature common to virtually all prostate cancers is the presence of only a single cell type without a basal cell layer. cytoplasmic. With the loss of glandular differentiation and the formation of cribriform structures. The recognition of basal cells on hematoxylin and eosin stained sections is not straightforward. with sparing of ejaculatory duct epithelium and lumen. with tracking along nerve. or isolated individual cells characterize undifferentiated prostate cancer. into periprostatic adipose tissue. tectural. B Adenocarcinoma of the prostate with focal extra-prostatic extension. Fig. to poorly differentiated tumours. radiate in columns out from the urethra in a linear fashion.A B Fig. contain a basal cell layer beneath the secretory cells. difficult to identify as being of prostatic origin. Another pattern characteristic of an infiltrative process is the presence of small atypical glands situated in between larger benign glands. B Ejaculatory duct invasion by prostatic adenocarcinoma.14 Limited adenocarcinoma of the prostate on needle biopsy. in contrast. With the exception of three malignant specific features listed at the end of this section. The histopathology of prostatic cancer.13 A Intraprostatic lymphovascular space invasion by prostatic adenocarcinoma. while more commonly seen in cancer. all of the features listed below. with duct wall invasion. there may be cells that closely mimic basal cells. 3. can also be seen in benign mimickers of cancer. rests on a constellation of archi- Architectural features Benign prostatic glands tend to grow either as circumscribed nodules within benign prostatic hyperplasia. Fig.

high- grade prostate cancer. show little variabilility in nuclear shape or size from one nucleus to another. there are only three features that are in and of themselves diagnostic of cancer. even in cancers which lack glandular differentiation. These are dense eosinophilic crystal-like structures that appear in various geometric shapes such as rectangular. Rarely. yet are infrequent in lower grade tumours. In most prostate cancers. Neoplastic glands may have amphophilic cytoplasm. as they have not been described in benign prostatic A B Acinar adenocarcinoma 171 Fig. especially lowgrade cancer {703}. typically seen in the terminal disseminated phase of the disease. In contrast. B Apocrine-like cytoplasmic blebing in prostatic adenocarcinoma glands. Fig. although exceptions occur. Malignant specific features Short of seeing prostatic glands in an extra-prostatic site. similar to benign glands. reveals marked nuclear pleomorphism. In contrast.pale-clear. Nuclear features Nuclei in prostate cancer range from those indistinguishable from benign prostatic epithelium to those with overt malignancy. yet are enlarged and hyperchromatic. there are cytological differences in the malignant glands when compared to the surrounding benign glands. since they are often Intraluminal features A feature more commonly seen in low grade prostate cancer. corpora amylacea. Prostate cancer cytoplasm of all grades typically lacks lipofuscin. are common in benign glands and only rarely seen in prostate cancer {2204}. the extent of nuclear atypia correlates with the architectural degree of differentiation. Nuclear enlargement with prominent nucleoli is a frequent finding. sharp luminal border without undulations or ruffling of the cytoplasm.16 Adenocarcinoma with amphophilic cytoplasm and enlarged nuclei containing prominent nucleoli. equivalently sized benign glands have an irregular luminal surface with small papillary infoldings and a convoluted appearance. Crystalloids. Intraluminal pink acellular dense secretions or blue-tinged mucinous secretions seen in hematoxylin and eosin stained sections are additional findings seen preferentially in cancer. Some neoplastic nuclei lack prominent nucleoli. . although not diagnostic of carcinoma. 3. as opposed to higher grade cancer is prostatic crystalloids {1111. in contrast to its presence in some benign prostatic glands {314}. hexagonal. triangular and rod-like structures. are more frequently found in cancer than in benign glands. Typically.2204}. Cytoplasmic features Glands of adenocarcinoma of the prostate tend to have a discrete crisp. although not every cancer cell will display these features. Cytoplasmic features of low grade prostate cancer are also often not very distinctive. which may be a useful diagnostic criterion of malignancy. 3. The one condition that mimics cancer where crystalloids are frequently seen is adenosis (atypical adenomatous hyperplasia) {843}. which consists of well-circumscribed round to oval structures with concentric lamellar rings. Prostate cancer nuclei. The finding of apical snouts is not helpful in distinguishing benign versus malignant glands as they can be seen in both. Mitotic figures may be relatively common in high-grade cancer.17 A Well differentiated carcinoma with mild nuclear atypia.

B Adenocarcinoma with straight rigid luminal borders. PAP is primarily reserved for cases of suspected prostatic carcinoma in which the PSA stain is negative {849}. Because of its relatively high specificity for prostatic glandular cells. mucoepidermoid carcinoma. bladder adenocarcinoma. granulomatous prostatitis and malakoplakia {66. but less specific than the monoclonal antibody {309}. mucinous fibroplasia (collagenous micronodules). helping to separate prostatic intraepithelial neoplasia from basal cell hyperplasia and transitional cell metaplasia in equivocal cases {66. adenoid cystic carcinoma. Some prostatic adenocarcinomas lose PSA immunoreactivity following androgen deprivation or radiation therapy. PSA immunonegative prostatic adenocarcinomas. consisting of glands with a cribriform proliferation that is not transluminal. Immunoprofile Prostate specific antigen (PSA) Following PSA’s discovery in 1979.1863}. Typically adencarcinoma of the prostate does not elicit a stromal inflammatory response. 3. Prostate specific membrane antigen (PSMA) (membrane bound antigen expressed in benign and malignant prostatic acinar cells) and androgen receptor may be immunoreactive in some high grade. paraffin-embedded tissue. PSA is a useful tissue marker expressed by most prostatic adenocarcinomas {66.702. salivary duct carcinoma).19 A Adenocarcinoma with blue-tinged mucinous secretions. salivary gland neoplasms (males) and mature teratoma {66.2905}. Whereas monoclonal antibodies to PSA do not label seminal vesicle tissue. mature teratoma. mesonephric duct remnants. mammary carcinoma. A minority of higher grade prostatic adenocarcinomas are PSA negative. these cribriform formations are attached to only one edge of the gland resulting in a structure superficially resembling a glomerulus. Cowper’s glands. Extraprostatic neoplasms and tumourlike conditions occasionally immunoreactive for PSA include urethral/periurethral adenocarcinoma (female). gastric parietal cells.2905}. 172 Tumours of the prostate . Extraprostatic tissues which are variably immunoreactive for PSA. gastrointestinal carcinoids). These are perineural invasion. urothelial glandular metaplasia (cystitis cystitica and glandularis). and glomerulations {160}.1676}. since a small number of prostatic adenocarcinomas are immunoreactive for only one of the two markers. although some of these tumours have been shown to express PSA mRNA. urachal remnants and neutrophils. 2374. seminal vesicle/ejaculatory duct glandular cells. but is neither expressed by basal cells. mammary carcinoma. such as seminal vesicle/ejaculatory duct epithelium. PAP and PSA have similar diagnostic utility. with both polyclonal and monoclonal antibodies available {702}. There is frequently intratumoural and intertumoural heterogeneity.702. include urethral and periurethral glands (male and female). Stromal features Ordinary acinar adenocarcinoma lacks a desmoplastic or myxoid stromal response. it has become a useful immunohistochemical marker of prostatic differentiation in formalin-fixed. 3. nor urothelial cells. salivary gland neoplasms in males (pleomorphic adenoma. Extraprostatic tissues reported to be immunoreactive for PAP include pancreatic islet cells. A Prostate specific acid phosphatase (PAP) Immunohistochemistry for PAP is active in formalin-fixed.1862.18 Intraluminal crystalloids in low grade adenocarcinoma. extramammary Paget disease of the penis.702. hepatocytes.2905}.2905}.glands. It is typified by very delicate loose fibrous tissue with an ingrowth of fibroblasts.1771. Reported PAP immunoreactive neoplasms include some neuroendocrine tumours (pancreatic islet cell tumours. PSA is also helpful in excluding benign mimics of prostatic carcinoma. such that evaluation of the stroma is typically not useful in the diagnosis of prostate cancer. urothelial adenocarcinoma. sometimes reflecting organization of intraluminal mucin. Fig. PSA in conjunction with a basal cell marker is useful in distinguishing intraglandular proliferations of basal cells from acinar cells. anal glands (male). PSA is localized to the cytoplasm of non-neoplastic prostatic glandular cells in all prostatic zones. The polyclonal antibody is more sensitive. PSA is diagnostically helpful in distinguishing prostatic adenocarcinomas from other neoplasms secondarily involving the prostate and establishing prostatic origin in metastatic carcinomas of unknown primary {702. and some nephrogenic adenomas {66.906}. some renal tubular epithelial cells and neutrophils. The final malignant specific feature is glomerulations.2905}. as can be seen in carcinoma {379. Although perineural indentation by benign prostatic glands has been reported.66. 702. anal cloacogenic carcinoma.1863. Rather.2905}. High molecular weight cytokeratins detected by 34βE12 (Cytokeratin-903) Prostatic secretory and basal cells are immunoreactive for antibodies to broad B Fig.309. paraffin-embedded tissues {26. and dense pink secretions. the glands in these cases appear totally benign and are present at only one edge of the nerve rather than circumferentially involving the perineural space. polyclonal antibodies have been shown to occasionally label seminal vesicle epithelium {2714}. with most studies indicating decreasing PSA expression with increasing tumour grade {702. The second specific feature for prostate cancer is known as either mucinous fibroplasia or collagenous micronodules. nephrogenic adenoma.

sweat duct. 3.g. absence of a basal cell layer is supportive of invasive carcinoma only in acinar proliferations which exhibit suspicious cytologic and / or architectural features on H&E stain {1048}. However. basal cell specific immunostains may help to distinguish invasive prostatic adenocarcinoma from benign small acinar cancer . B Prostate cancer with glomerulations. some early invasive prostatic carcinomas.g. salivary gland.918.20 A. One high molecular monoclonal cytokeratin antibody. microinvasive carcinomas arising in association with or independent of high grade prostatic intraepithelial neoplasia. Conversely. Immunohistochemistry for cytokeratins 7 and 20 have a limited diagnostic use in prostate pathology with the exception that negative staining for both markers. Rare prostatic adenocarcinomas contain sparse neoplastic glandular cells. clone 34βE12. 5.2905}.309. bronchial/pneumocyte.21 A Adenocarcinoma with perineural invasion.2374}. may have residual basal cells {1952}. e. and mesothelium {918}. recognizes 57 and 66 kilodalton cytokeratins in stratum corneum corresponding to Moll numbers 1. post-atrophic hyperplasia. Intraductal spread of invasive carcinoma and entrapped benign glands are other proposed explanations for residual basal cells {66. some intestinal and ductal epithelium (breast.A B Fig. and is widely used as a basal cell specific marker active in paraffin-embedded tissue following proteolytic digestion {66. The use of antibodies for 34βE12 is especially helpful for the diagnosis for of deceptively benign appearing variants of prostate cancer.1765.1048. only basal cells express high molecular weight cytokeratins {309}.2374. the complete absence of a basal cell layer in a small focus of acini cannot be used alone as a definitive criterion for malignancy. 3. which can occur in prostate Acinar adenocarcinoma 173 .2905}. 10 and 14. An immunoperoxidase cocktail containing monoclonal antibodies to cytokeratins 5 and 6 is also an effective basal cell stain {1286}. 34βE12 is also immunoreactive against squamous. thymic.1048. Because the basal cell layer may be interrupted or not demonstrable in small numbers of benign glands. sclerosing adenosis and radiation induced atypia {66. adenosis (atypical adenomatous hyperplasia). spectrum and low molecular weight cytokeratins. A B Fig.mimics which retain their basal cell layer. urothelial. e. rather. glandular atrophy. Since uniform absence of a basal cell layer in prostatic acinar proliferations is one important diagnostic feature of invasive carcinoma and basal cells may be inapparent by H&E stain. yet these are not in a basal cell distribution {66. renal collecting duct). bile duct. pancreas. which are immunoreactive for 34βE12. B Adenocarcinoma with mucinous fibroplasia (collagenous micronodules).2905}.

bronchial). breast and urogenital tract. a nuclear protein encoded by a gene on chromosome 3q27-29 with homology to p53 (a tumour suppressor gene). PSA transcription in secretory cells and promoting cellular proliferation. AR immunoreactivity was demonstrated in a minority (42. one study demonstrated that 85% of untreated 174 Tumours of the prostate . and treated carcinoma show lower AMACR expression {2936}.2856. stromal cells.have occasional p63 immunoreactive cells.embedded tissue {187. B Metastatic adenocarcinoma to a supraclavicular lymph node labeled staining positively for prostate specific antigen. AMACR is not specific for prostate cancer and is present in nodular hyperplasia (12%).g. Certain subtypes of prostate cancer.1220. p63 p63. salivary glands. AR monoclonal and polyclonal antibodies are active in formalin-fixed. atrophic carcinoma. high grade PIN (>90%) {2935}. mediating androgen dependent cellular functions. e. cutaneous apocrine/eccrine glands). However.5%) {2869}. p63 has similar applications to those of high molecular weight cytokeratins in the diagnosis of prostatic adenocarcinoma. Positive nuclear staining indicates immunoreactive protein. 3. atrophic glands.2935}. Note nuclear labeling of basal cells in adjacent benign glands D Positive staining for racemase in adenocarcinoma of the prostate. paraffin. but with the advantages that p63: 1) stains a subset of 34βE12 negative basal cells. reserve cells of simple columnar epithelia (endocervical. Most invasive prostatic adenocarcinomas are immunoreactive for AR.5%) cases of high grade prostatic intraepithelial neoplasia. myoepithelial cells (breast. Specific isotypes are expressed in basal cells of pseudostratified epithelia (prostate. Interpretative limitations related to presence or absence of basal cells in small numbers of glands for 34βE12 apply to p63. A monoclonal antibody is active in paraffinembedded tissue following antigen retrieval. AMACR may be used as a confirmatory stain for prostatic adenocarcinoma. pancreatic ductal). has been shown to regulate growth and development in epithelium of the skin. most representing entrapped benign glands or intraductal spread of carcinoma with residual basal cells {1286}. and 3) is easier to interpret because of its strong nuclear staining intensity and low background.1593}. Note cytoplasmic labeling of basal cells in adjacent benign glands. Immunohistochemical studies on biopsy material with an antibody directed against AMACR (P504S) demonstrate that over 80% of prostatic adenocarcinomas are labeled {1221. urothelium and squamous epithelium {1286}. adenocarcinoma. would be unusual for transitional cell carcinoma {849}.2559}. 3. paraffin-embedded tissue following antigen retrieval {1592. The activated protein serves as a transcription factor. B Negative staining for high molecular weight cytokeratin in prostate cancer. and adenosis (atypical adenomatous hyperplasia) (17. in conjunction with H&E morphology and a basal cell specific marker {2935}. C Negative staining for p63 in prostate cancer. requiring correlation with morphology {2374}. Prostatic adenocarcinomas A B C D Fig. for which polyclonal and monoclonal antibodies have been produced which are active in formalin-fixed. Androgen receptor (AR) AR is a nuclear localized. but does not distinguish active from inactive forms of the protein. androgen binding protein complex occurring in prostatic glandular. This mRNA was found to encode a racemase protein.23 A H & E stain of adenocarcinoma of the prostate.22 A Prostate specific antigen (PSA) expression in prostatic adenocarcinoma with accentuation of glandular luminal spaces. pseudohyperplastic. such as foamy gland carcinoma. basal. A B Fig. 2) is less susceptible to the staining variability of 34βE12 (particularly in TURP specimens with cautery artefact). α-Methyl-CoA racemase (AMACR) AMACR mRNA was recently identified as being overexpressed in prostatic adenocarcinoma by cDNA library subtraction utilizing high throughput RNA microarray analysis {2856}. AMACR is expressed in other non-prostatic neoplasms including urothelial and colon cancer. cervix.

24 Atrophic adenocarcinoma. It is almost always helpful to verify pseudohyperplastic cancer with the use of immunohistochemistry to verify the absence of basal cells. The presence of cytologic atypia in some of these glands further distinguishes them from benign glands. First. A Note the microcystic pattern and B the prominent nucleoli. foamy gland cancer is seen in association with ordinary A B Acinar adenocarcinoma 175 Fig. back-to-back with straight even luminal borders. One pattern of pseudohyperplastic adenocarcinoma consists of numerous large glands that are almost Foamy gland variant Foamy gland cancer is a variant of acinar adenocarcinoma of the prostate that is characterized by having abundant foamy appearing cytoplasm with a very low nuclear to cytoplasmic ratio. A characteristic finding in some benign cases of atrophy is the presence of a centrally dilated atrophic gland surrounding by clustered smaller glands. and abundant cytoplasm. Pseudohyperplastic variant Pseudohyperplastic prostate cancer resembles benign prostate glands in that the neoplastic glands are large with branching and papillary infolding {1146. 1485}.2559}. atrophic prostate cancers are usually unassociated with such a prior history {467. Atrophic prostate cancer may also be differentiated from benign atrophy by the presence of marked cytologic atypia. Atrophic variant As described under histopathology. However. . An unusual variant of prostate cancer resembles benign atrophy owing to its scant cytoplasm. 3. suggesting one mechanism of androgen resistance may be AR loss {1592. The diagnosis of carcinoma in these cases may be based on several features. extraprostatic extension). Finally. are associated with fibrosis. Atrophy may show enlarged nuclei and prominent nucleoli. atrophic prostate cancer may demonstrate a truly infiltrative process with individual small atrophic glands situated between larger benign glands. Because androgen insensitivity may occur without loss of AR immunoreactivity. although not the huge eosinophilic nucleoli seen in some atrophic prostate cancers. which has been termed "post-atrophic hyperplasia (PAH)" {83}. Pseudohyperplastic cancer. they are not truly infiltrative. it does not contain lipid. despite its benign appearance. Histologic variants The following histologic variants of prostate adenocarcinoma are typically seen in association with ordinary acinar adenocarcinoma.prostate adenocarcinomas exhibit AR immunoreactivity in greater than 50% of tumour cells. more so than those of benign prostatic secretory cells. In contrast. with increasing heterogeneity occurring with increasing histologic grade and pathologic stage {1592}. Although ordinary prostate cancers may develop atrophic cytoplasm as a result of treatment (see carcinoma affected by hormone therapy).. as individual benign atrophic glands are not seen infiltrating in between larger benign glands. the entire sampled tumour may demonstrate only the variant morphology. Imumunostaining for AR is not in routine clinical use. More typical cytological features of adenocarcinoma such as nuclear enlargement and prominent nucleoli are frequently absent. positive AR immunophenotype may not reliably distinguish androgen dependent from independent tumours {1592}. but rather empty vacuoles {2637}. benign atrophy has a lobular configuration. Characteristically. on limited biopsy material. Although the cytoplasm has a xanthomatous appearance. Although the glands of benign atrophy may appear infiltrative on needle biopsy.664}. and frequently present dense pink acellular secretions {1880}. which makes this lesion difficult to recognize as carcinoma especially on biopsy material. In most cases. the concomitant presence of ordinary less atrophic carcinoma can help in recognizing the malignant nature of the adjacent atrophic cancer glands. it is recognized as carcinoma by its architectural pattern of crowded and/or infiltrative glands. may be associated with typical intermediate grade cancer and can exhibit aggressive behaviour (ie. atrophic prostate cancer lack such a desmoplastic stromal response. Comparably sized benign glands either have papillary infoldings or are atrophic. Whereas some forms of atrophy. The recognition of cancer with this pattern is based on the architectural pattern of numerous closely packed glands as well as nuclear features more typical of carcinoma. most prostate cancers have abundant cytoplasm. the nuclei in foamy gland carcinoma are small and densely hyperchromatic. Some studies have shown AR heterogeneity or loss in a subset of AR independent tumours. Nuclei in foamy gland cancer are round. In addition to the unique nature of its cytoplasm.

On biopsy material. Some carcinomas of the prostate will have a signet-ring-cell appearance. Mucinous (colloid) adenocarcinoma of the prostate gland is one of the least common morphologic variants of prostatic carcinoma {710. cancers with abundant extracellular mucin should be diagnosed as carcinomas with mucinous features. showing prominent nucleoli. in single glands. the diagnosis of mucinous adenocarcinoma of the prostate gland should be made when at least 25% of the tumour resected contains lakes of extracellular mucin. adenocarcinoma of the prostate. B Pseudohyperplastic adenocarcinoma with prominent nucleoli (arrow).26 A Cancer of pseudohyperplastic type. . These tumours have been negative immunohistochemically for PSA and PAP. mucin-containing signet cells.2660}. Branding and pepillary type of and growth is typical. as the biopsy material may not be reflective of the entire tumour. In almost all such cases. The histologic growth pattern found in these tumours were identical to mucinous adenocarcinoma of the bladder consisting lakes of mucin lined by tall columnar epithelium with goblet cells showing varying degrees of nuclear atypia and in some of these cases. the ordinary adenocarcinoma component is not low grade. despite foamy glands cancer’s benign cytology. Even more rare are cases of in-situ and infiltrating mucinous adenocarcinoma arising from glandular metaplasia of the prostatic urethra with invasion into the prostate {2636}. 3. C Higher magnification.2207. In contrast to bladder adenocarcinomas. Crowded glands with too little stroma to be a BPH. foamy gland carcinoma appears best classified as intermediate grade carcinoma. 3. and in sheets of cells. Consequently. Only a few cases of prostate cancer have been reported with mucin positive signet cells {1057. yet the vacuoles do not contain intracytoplasmic mucin {2206}. A cribriform pattern tends to predominate in the mucinous areas.A B C Fig. B Perineural invasion. Colloid & signet ring variant Using criteria developed for mucinous carcinomas of other organs. One should exclude other mucinous tumours of non-prostatic origin based on morphology and immunohistochemistry and if necessary using clinical information. rather than colloid carcinoma.25 A Pseudohyperplastic adenocarcinoma. A 176 Tumours of the prostate B Fig. mucinous adenocarcinoma of the prostate rarely contain mucin positive signet cells. These vacuolated cells may be present as singly invasive cells.2274}.

In the largest reported series. Malignant cells are A Fig. Although these tumours are not as hormonally responsive as their nonmucinous counterparts. some respond to androgen withdrawal. 3. Mucinous prostate adenocarcinomas behave aggressively {710. 3. Tumour cells have round to ovoid hyperchromatic nuclei. elevated serum PSA {2080} and metastasis of similar morphology {1972} have been reported. Lymphoepithelioma-like variant This undifferentiated carcinoma is characterized by a syncytial pattern of malignant cells associated with a heavy lymphocytic infiltrate.30 A Mucinous adenocarcinoma. Oncocytic variant Prostatic adenocarcinoma rarely is composed of large cells with granular eosinophilic cytoplasm. 3. 3.29 Adenocarcinoma of the prostate with signet-ring cell-like features.2080}.A Fig. colloid variant left part. A high Gleason grade {1972.28 A Colloid adenocarcinoma. Mucinous prostate adenocarcinomas have a propensity to develop bone metastases and increased serum PSA levels with advanced disease. B A B Fig. B Foamy gland adenocarcinoma. B Fig.2207. and are strongly positive for PSA. B Colloid carcinoma. 7 of 12 patients died of tumour (mean 5 years) and 5 were alive with disease (mean 3 years).2274}.27 A. Acinar adenocarcinoma 177 . B Acinar adenocarcinoma of the prostate. Numerous mitochondria are seen on ultra- structural examination.

Biopsy findings predict prognosis with positive biopsies showing no treatment effect having a worse outcome than negative biopsies. Following radiation therapy. Paradoxically the nuclear atypia in prostate carcinoma showing radiation effect is less than that seen in radiation atypia of benign glands. these areas may be difficult to identify.PSA positive.2145}.1578}. cancer showing no or minimal radiation effect. rhabdomyosarcoma. In some series.2376}.644.2093}. chondrosarcoma. 3. The stroma is often sclerosed. which can be overlooked in H&E stained sections. In the latter the stromal hyalinization is often sharply delineated. Treatment effects Radiation therapy Radiation therapy can be given as either external beam or interstitial seed implants or as a combination of the two. Hormone therapy The histology of prostate cancer may be significantly altered following its treatment with hormonal therapy {2358}. . Serum PSA is within normal limits in most cases. Architecturally. Radiation therapy affects prostate cancer variably with some glands showing marked radiation effect and others showing no evidence of radiation damage. Microscopically. resulting in clustered cells or individual cells. benignappearing bone or cartilage in the stroma.2093}. angiosarcoma or multiple types of heterologous differentiation {644.1060.1061. In situ hybridization has been negative for Epstein-Barr virus {34}.31 A Sarcomatoid carcinoma with adenosquamous carcinoma. whereas spindle-cell elements react with markers of soft tissue tumours and variably express cytokeratins. Associated acinar adenocarcinoma has been noted {34.1086. tumour cells with treatment effect are usually positive for PAP and PSA. Although there exists various systems to grade radiation effects. or cancer showing significant radiation effect. There is less than a 40% five-year survival {644}. A related pattern is the presence of individual tumour cells resembling inflammatory cells. In some areas. and often the only clue to areas of hormonally treated carcinoma is a fibrotic background with scattered larger cells.1555.1065. Amongst the specific mesenchymal elements are osteosarcoma. Cytologically. Clinical significance is uncertain. sometimes resulting in empty clefts. 1584}. By immunohistochemistry.2175. particularly following radioactive seed implantation. carcinosarcoma and sarcomatoid carcinoma are considered as separate entities based on the presence of specific mesenchymal elements in the former.588. However. Sarcomatoid carcinoma of the prostate is a rare neoplasm composed of both malignant epithelial and malignant spindle-cell and/or mesenchymal elements {207. After radiation therapy the prostate gland is usually small and hard. These antibodies along with pan- cytokeratins are very helpful to detect isolated residual tumour cells. increased in volume and often vacuolated. prostatic biopsy should be diagnosed as no evidence of cancer. these two lesions are best considered as one entity. these are not recommended for routine clinical practice. Sarcomatoid variant (carcinosarcoma) There is considerable controversy in the literature regarding nomenclature and histogenesis of these tumours. or a combination of the above. Sarcomatoid carcinoma should be distinguished from the rare carcinoma with metaplastic. there may be only scattered cells within the stroma resembling foamy histiocytes with pyknotic nuclei and xanthomatous cytoplasm. the cytoplasm of the tumour cells is pale. given their otherwise similar clinico-pathologic features and identically poor prognosis. These cells then desquamate into the lumen of the malignant glands where they resemble histiocytes and lymphocytes. The sarcomatoid component often consists of a nonspecific malignant spindle-cell proliferation.842. Nucleoli are often lost {607. carcinoma showing treatment effect typically loses their glandular pattern.1578. B Sarcomatoid carcinoma with osteoid formation. epithelial elements react with antibodies against PSA and/or pan-cytokeratins. By immunohistochemistry. One pattern is that neoplastic glands develop pyknotic nuclei and abundant xanthomatous cytoplasm. The gross appearance often resembles sarcomas. sarcomatoid carcinoma is composed of a glandular component showing variable Gleason score {644. Nodal and distant organ metastases at diagnosis are common {644. There is often a greater variation of nuclear size than in non-irradiated prostate cancer and the nuclei may be pyknotic or large with clumped chromatin. Sarcomatoid carcinoma may be present in the initial pathologic material (synchronous presentation) or there may be a previous history of adenocarcinoma treated by radiation and/or hormonal therapy {1578}. leiomyosarcoma. liposarcoma. A 178 Tumours of the prostate B Fig. and cancer with treatment effect having an intermediate prognosis {511}. At low power.

The Gleason grading system is based on glandular architecture. the most prevalent and the second most prevalent pattern are added to obtain a Gleason score or sum. The Gleason grading system defines five histological patterns or grades with decreasing differentiation. the grade of the tumour appears artefactually higher.2447. Gleason score is obtained by doubling that pattern. A B Fig. and in 1993. Gleason score 3+3=6. and also whether prostate cancer should be graded according to its least differentiated or dominant pattern. The primary and secondary pattern. It is recommended that the primary and secondary pattern as well as the score be reported. identical to untreated prostate cancer. with areas of the cancer appearing unaffected {117. it was recommended by a WHO consensus conference {1840}. 3.32 A Sarcomatoid carcinoma. there is an almost total loss of polarity with only occasional luminal differentiation. correlates with prognosis of prostate cancer but there is no convincing evidence that it adds independent prognostic information to that obtained by grading glandular differentiation alone {1801}.g. Gleason scores 2 and 3 are only exceptionally Acinar adenocarcinoma 179 .g. Cancer cells following hormonal therapy demonstrate a lack of high molecular weight cytokeratin staining. Immunohistochemistry for PSA or pancytokeratin can aid in the diagnosis of carcinoma in these cases by identifying the individual cells as epithelial cells of prostatic origin.340.2176. 1059. If the tumour only has one pattern. B Adenocarcinoma with cancer showing radiation effect adjacent to cancer without evidence of radiation effect.2681}. In patterns 1 to 3. The main controversies have been whether grading should be based on glandular differentiation alone or a combination of glandular differentiation and nuclear atypia. Normal prostate epithelial cells are arranged around a lumen. Note both epithelial (upper centre) and mesenchymal differentiation.33 A Cancer with radiation effect. Following a response to combination endocrine therapy. i.1852. e. The degenerating tumour cells are ballooned. Gleason is now the predominant grading system.e. nuclear atypia is not evaluated {894. Prostate cancer has a pronounced morphological heterogeneity and usually more than one histological pattern is present. Note pleomorphic hyperchromatic nuclei. In pattern 4. The Gleason grading system named after Donald F.470. 3. B High-magnification view of spindle cell component of sarcomatoid carcinoma of prostate. Gleason score 3+4=7. there is partial loss of normal polarity and in pattern 5. As with radiation. Gleason grading system Numerous grading systems have been designed for histopathological grading of prostate cancer. when compared to the grade of the pretreated tumour. the response to hormonal therapy may be variable.895}.A B Fig. there is retained epithelial polarity with luminal differentiation in virtually all glands. Nuclear atypia as adopted in some grading systems. e.

B B uated in Gleason grading. C Tumour cells are vacuolated. D. C Fig. In needle biopsy material. Fused glands are composed of a group of glands that are no longer completely separated by stroma. closely packed glands. because Gleason pattern 1 is unusual. it is usually only a minor component of the tumour and not included in the Gleason score. but there may also be large. Each gland has an open lumen and is circumscribed by stroma. cribriform or they may be poorly defined. Cribriform pattern 3 is rare and difficult to distinguish from cribriform high-grade PIN. The glands are of intermediate size and larger than in Gleason pattern 3. it has been proposed that a Gleason score of 2-4 should not be assigned {704. Gleason. When present. The glands are more infiltrative and the distance between them is more variable than in patterns 1 and 2. the glands appear fused. Gleason score 4 is also relatively uncommon because pattern 2 is usually mixed with some pattern 3 resulting in a Gleason score 5.F. The glands of pattern 3 vary in size and shape and are often angular. Malignant glands often infiltrate between adjacent non-neoplastic glands. Gleason pattern 1 Gleason pattern 1 is composed of a very well circumscribed nodule of separate. The glands are of intermediate size Gleason pattern 2 Gleason pattern 2 is composed of round or oval glands with smooth ends. there are no strands of stroma within a cribriform gland. Gleason pattern 2 is usually seen in transition zone cancers but may occasionally be found in the peripheral zone. the cytoplasm of Gleason pattern 1 and 2 cancers is abundant and pale-staining. B In the center a group of tumour cells with eosinophilic granular cytoplasm indicating paracrine-endocrine differentiation. There may be minimal invasion by neoplastic glands into the surrounding non-neoplastic prostatic tissue. C Fig. C Isolated tumour cells following anti-androgen therapy expressing pancytokeratin. The variation in glandular size and separation between glands is less than that seen in pattern 3. The edge of a group of fused glands is scalloped and there are occasional thin strands of connective tissue within this group. Poorly defined glands do not have a lumen that is completely encircled by epithelium.2283}. Gleason pattern 1 is exceedingly rare.35 A Adenocarcinoma following anti-androgen therapy with tumour undergoing pyknosis.36 Schematic diagram of the Gleason scoring system. Gleason score 2-4 tumour may be seen in TURP material sampling the transitional zone. and approximately equal in size and shape. 3. As opposed to fused glands. Small glands are typical for pattern 3.A A Fig. Most cribriform invasive cancers should be assigned a pattern 4 rather than pattern 3. assigned. This pattern is usually seen in transition zone cancers. irregular glands. clear with focal loss of cell membranes. created by Dr. Gleason pattern 3 Gleason pattern 3 is the most common pattern. Gleason pattern 4 In Gleason pattern 4.34 A Anti-androgen therapy induced tumour suppression leading to cystic spaces. 3. Gleason scores 6 and 7 are the most common scores and include the majority of tumours in most studies. Surrounding tumour cells are degenerated. 3. which do not infiltrate into adjacent benign prostatic tissue. Cribriform pattern 4 glands are large or they may be irregular with jagged edges. B Adenocarcinoma following anti-androgen therapy with tumour undergoing pyknosis leading to tumour resembling foamy histiocytes. The glands are more loosely arranged and not quite as uniform in size and shape as those of Gleason pattern 1. Although not eval- 180 Tumours of the prostate .

the clinician may misconstrue this as the Gleason score. Only occasional lumina may be seen. If only the pattern is reported. The epithelium forms solid sheets. the prognosis is not necessarily equated to the addition of the primary Gleason pattern and the tertiary highest Gleason pattern. In radical prostatectomy specimens. It has been demonstated that some tumours are high grade when they are small {707}. The correlation between biopsy and prostatectomy Gleason score is equivalent or only marginally worse with minimal cancer on Tertiary Gleason patterns The original Gleason grading system does not account for patterns occupying less than 5% of the tumour or for tertiary patterns. It is recommended that a Gleason score be reported even when a minimal focus of cancer is present. solid strands or single cells invading the stroma. Tumour grade is on average higher in larger tumours {1688}. the presence of a tertiary high grade component adversely affects prognosis.2498}. For example. The hypernephromatoid pattern described by Gleason is a rare variant of fused glands with clear or very palestaining cytoplasm.38 A Prostate cancer Gleason pattern 2. because the patients have undergone a repeat transurethral resection or repeat biopsy due to symptoms of tumour progression {526}.A B Fig. it is not Acinar adenocarcinoma 181 . biopsy {668. Comedonecrosis may be present. 3. It is recommended that even in small cancers with one Gleason pattern that the Gleason score be reported. Grading minimal cancer on biopsy. However. B Prostate cancer Gleason pattern 2. A B Fig. In patients followed expectantly there is no evidence of grade progression within 1-2 years {717}. Gleason score 1+1=2 with numerous crystalloids.37 A Gleason score 1+1=2. Gleason pattern 5 In Gleason pattern 5. Many studies addressing the issue of grade progression have a selection bias. The observed grade progression may be explained by a growth advantage of a tumour clone of higher grade that was present from the beginning but undersampled. the presence of a tertiary Gleason pattern 5 in a Gleason score 4+3=7 tumour worsens the prognosis compared to the same tumour without a tertiary high grade component. Grade progression The frequency and rate of grade progression is unknown. However. However. 3. B Well-circumscribed nodule of prostatic adenocarcinoma. this may be due to more rapid growth of high grade cancers. there is an almost complete loss of glandular lumina. Care must be applied when assigning a Gleason pattern 4 or 5 to limited cancer on needle biopsy to exclude an artefact of tangential sectioning of lower grade cancer.2257.

Crush artefacts are common at the margins of prostatectomy specimens and in core biopsies. 4 and 5 also present. B Gleason pattern 3 with small glands. and that sampling artefact accounts for its limited nature on biopsy. most clinicians take the highest Gleason score when planning treatment options. it should be reported in addition to the Gleason score. Although comparable data do not currently exist for needle biopsy material. In cases with a minor component of a prostate cancer variant. it is controversial whether to assign an averaged (composite) Gleason score or whether the highest Gleason score should be considered as the patient’s grade {1407}. Crushed areas should not be Gleason graded. B associated with as adverse prognosis as a Gleason score 4+5=9 {2005}.40 A Cribriform Gleason score 3+3=6. When this tertiary pattern is pattern 4 or 5. An alternative option is in the situation with a tertiary high grade pattern (i.42 Gleason score 4+4=8. tional prostate cancer and their effect on prognosis is difficult to estimate. Gleason grading should be based on the conventional prostate cancer present in the specimen. 3.41 Gleason pattern 3 prostatic adenocarcinoma with amphophilic to cleared cytoplasm. pyknotic nuclei adjacent to preserved cells. Prostate cancer showing either hormonal or radiation effects can appear artefactu- A B Fig.A Fig.39 A Gleason score 3+3=6. mucinous and ductal cancer). it is controversial whether to assign a Gleason grade. 3. Reporting Gleason scores in cases with multiple positive biopsies In cases where different positive cores have divergent Gleason scores. In practice. Crush artefacts cause disruption of the glandular units and consequently may lead to overgrading of prostate cancer. 3. the highest grade is incorporated as the secondary pattern. B Prostate cancer Gleason pattern 3 of cribriform type. They are almost always combined with conven- Grading of specimens with artefacts and treatment effect Crush artefacts. In the rare case where the variant form represents the major component. 3+4+5 or 4+3+5) is to diagnose the case as Gleason score 8 with patterns 3. These artefacts are recognized by the presence of noncohesive epithelial cells with fragmented cytoplasm and dark. in the setting of three grades on biopsy where the highest grade is the least common. Hormonal and radiation treatment. 3.e. even when it is less than 5% of the tumour. The assumption is that a small focus of high grade cancer on biopsy will correlate with a significant amount of high grade cancer in the prostate such that the case overall should be considered high grade. Grading of variants of prostate cancer Several morphological variants of prostate adenocarcinoma have been described (e. Fig. Fig.g. 182 Tumours of the prostate .

45 A Gleason score 5+5=10. Several studies have compared biopsy Acinar adenocarcinoma 183 . 58% have a single grade. B Prostate cancer Gleason pattern 4 with irregular cribriform glands. 3. A Fig. Of individual tumour foci.43 A Prostate cancer Gleason pattern 4 with fusion of glands. If there is cancer that does not show treatment effect.44 A Gleason score 5+5=10 with comedonecrosis. 3. B ally to be of higher Gleason score. Consequently. a Gleason score can be assigned to these components.A B Fig. B Gleason pattern 5 with solid strands. but most of these foci are very small {2261}. and cancer of a single grade is present in only 16% of the specimens {2261}. Prostate cancer displays a remarkable degree of intratumoural grade heterogeneity. Gleason grading of these cancers should not be performed. A B Fig. Over 50% of total prostatectomy specimens contain cancer of at least three different Gleason grades {41}. B Gleason score 5+5=10 with comedonecrosis. Correlation of needle biopsy and prostatectomy grade. 3.

and prostatectomy Gleason score {375,668,2498}. Exact correlation has been observed in 28.2-67.9% of the cases. The biopsies undergraded in 24.560.0% and overgraded in 5.2-32.2%. Causes for biopsy grading discrepencies are undersampling of higher or lower grades, tumours borderline between two grade patterns, and misinterpretation of patterns {2498}. The concordance between biopsy and prostatectomy Gleason score is within one Gleason score in more than 90% of cases {668}.

Reproducibility Pathologists tend to undergrade {665,2498}. The vast majority of tumours graded as Gleason score 2 to 4 on core biopsy are graded as Gleason score 5 to 6 or higher when reviewed by experts in urological pathology {2498}. In a recent study of interobserver reproducibility amongst general pathologists, the overall agreement for Gleason score groups 2-4, 5-6, 7, and 8-10 was just into the moderate range {67}. Undergrading is decreased with teaching efforts and a substantial interobserver reproducibility can be obtained {665,1400}. Prognosis Multiple studies have confirmed that Gleason score is a very powerful prognostic factor on all prostatic samples. This includes the prediction of the natural history of prostate cancer {54,667} and the assessment of the risk of recurrence after total prostatectomy {713,1144} or radiotherapy {937}. Several schedules for grouping of Gleason scores in prognostic categories have been proposed.

Gleason scores 2 to 4 behave similarly and may be grouped. Likewise, Gleason scores 8 to 10 are usually grouped together, although they could be stratified with regard to disease progression in a large prostatectomy study {1446}. There is evidence that Gleason score 7 is a distinct entity with prognosis intermediate between that of Gleason scores 5-6 and 8 to 10, respectively {667,2590}. Although the presence and amount of high grade cancer (patterns 4 to 5) correlates with tumour prognosis, reporting the percentage pattern 4/5 is not routine clinical practice {666,2479}. Gleason score 7 cancers with a primary pattern 4 have worse prognosis than those with a primary pattern 3 {406,1447,2282}. Genetics In developed countries, prostate cancer is the most commonly diagnosed nonskin malignancy in males. It is estimated that 1 in 9 males will be diagnosed with prostate cancer during their lifetime. Multiple factors contribute to the high incidence and prevalence of prostate cancer. Risk factors include age, family history, and race. Environmental exposures are clearly involved as well. Although the exact exposures that increase prostate cancer risk are unclear, diet (especially those high in animal fat such as red meat, as well as, those with low levels of antioxidants such as selenium and vitamin E) job/industrial chemicals, sexually transmitted infections, and chronic prostatitis have been implicated to varying degrees. The marked increase in incidence in prostate cancer that occurred in the mid 1980s, which subsequently leveled off in the

mid to late 1990s, indicates that wide spread awareness and serum prostate specific antigen screening can produce a transient marked increase in prostate cancer incidence.

Hereditary prostate cancer Currently the evidence for a strong genetic component is compelling. Observations made in the 1950s by Morganti and colleagues suggested a strong familial predisposition for prostate cancer {1784}. Strengthening the genetic evidence is a high frequency for prostate cancer in monozygotic as compared to dizygotic twins in a study of twins from Sweden, Denmark, and Finland {1496}. Work over the past decade using genome wide scans in prostate cancer families has identified high risk alleles, displaying either an autosomal dominant or X-linked mode of inheritance for a hereditary prostate cancer gene, from at least 7 candidate genetic loci. Of these loci, three candidate genes have been identified HPC2/ELAC2 on 17p {2584}, RNASEL on 1q25 {377}, and MSR1 on 8p22-23 {2857}. These 3 genes do not account for the majority of hereditary prostate cancer cases. In addition, more than 10 other loci have been implicated by at least some groups. The discovery of highly penetrant prostate cancer genes has been particularly difficult for at least 2 main reasons. First, due to the advanced age of onset (median 60 years), identification of more than two generations to perform molecular studies on is difficult. Second, given the high frequency of prostate cancer, it is likely that cases considered to be hereditary during segregation studies actually repre-

A
Fig. 3.46 A Gleason score 3+4=7. B Gleason score 3+4=7.

B

184 Tumours of the prostate

Fig. 3.48 Heat map-nature. From S.M. Dhanasekaran et al. {604}.

Fig. 3.47 Meta-analysis heat map. From D.R. Rhodes et al. {2183a}.

Fig. 3.49 Gleason score 7 tumours comprise a large percentage of prostate cancer in the radical prostatectomy specimens, and constitute an intermediate category in terms of prognosis between Gleason scores of 6 and those of 8. Within the score 7 tumours, the proportion of Gleason pattern 4 carcinoma is important, i.e. (4+3) are more aggressive than (3+4) tumours.

sent phenocopies; currently it is not possible to distinguish sporadic (phenocopies) from hereditary cases in families with high rates of prostate cancer. In addition, hereditary prostate cancer does not occur in any of the known cancer syndromes and does not have any clinical (other than a somewhat early age of onset at times) or pathologic characteristics to allow researchers to distinguish it from sporadic cases {302}. Perhaps even more important in terms of inherited susceptibility for prostate can-

cer are common polymorphisms in a number of low penetrance alleles of other genes - the so-called genetic modifier alleles. The list of these variants is long, but the major pathways currently under examination include those involved in androgen action, DNA repair, carcinogen metabolism, and inflammation pathways {2246,2858}. It is widely assumed that the specific combinations of these variants, in the proper environmental setting, can profoundly affect the risk of developing prostate cancer.

Molecular alterations in sporadic prostate cancer While mutations in any of the classic oncogenes and tumour suppressor genes are not found in high frequency in primary prostate cancers, a large number of studies have identified non-random somatic genome alterations. Using comparative genomic hybridization (CGH) to screen the DNA of prostate cancer, the most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q and gains at 1q, 2p, 7, 8q, 18q, and Xq {436,1246,1924,2737}. Numerous genes have now been implicated in prostate cancer progression. Several genes have been implicated in the earliest development of prostate cancer. The pi-class of Glutathione S-transferase (GST), which plays a caretaker role by normally preventing stress related damage, demonstrates hypermethylation in high percentage of prostate cancers, thus preventing expression of this protective gene {1465, 1505,1732}. NKX3.1, a homeobox gene located at 8p21 has also been implicated in prostate cancer {304,1047,1319, 2741}. Although no mutations have been identified in this gene {2741}, recent work suggests that decreased expression is associated with prostate caner progression {304}. PTEN encodes a phosphatase, active against both proteins and lipids, is also commonly altered in prostate cancer progression {1491, 2489}. PTEN is believed to regulate the phosphatidylinositol 3’-kinase/protein kinase B (PI3/Akt) signaling pathway and therefore mutations or alterations lead to tumour progression {2850}. Mutations are less common than initially thought in prostate cancer, however, tumour suppressor activity may occur from the loss of one allele, leading to decreased expresAcinar adenocarcinoma 185

Table 3.01 Prostate cancer susceptibility loci identified by linkage analysis Susceptibility loci Locus 1q24-25 1q42.2-43 1p36 Xq27-28 20q13 17p 8p22-23 Mode AD AD AD X-linked/AR AD AD AD Putative gene Reference {377,2451} {230} {871} {2855} {229} {2584} {2857}

HPC1 PCAP CAPB HPCX HPC20 HPC2

RNASEL
? ? ? ?

HPC2/ELAC2 MSR1

________ Key: Mode=suggested mode of inheritance; AD=autosomal dominant; AR=autosomal recessive.

Fig. 3.50 Paradigm for gene discovery.

sion of PTEN (i.e. haploinsufficiency) {1418}. A number of other genes have also been associated with prostate cancer including p27 {496, 975,2867} and E-cadherin {1989,2674}. p53 mutations are late events in prostate cancer and tend to occur in advanced and metastatic prostate tumours {1052}. Another very common somatic genomic alteration in prostate and other cancers is telomere shortening {1697,2461}. This molecular alteration is gaining heightened awareness as it has become clear that critically short telomere may lead to genetic instability and increased epithelial cancers in p53+/- mice {121,250}. Recent advances in genomic and proteomic technologies suggest that molecu-

lar signatures of disease can be used for diagnosis {33,907}, to predict survival {2238,2551}, and to define novel molecular subtypes of disease {2056}. Several studies have used cDNA microarrays to characterize the gene expression profiles of prostate cancer in comparison with benign prostate disease and normal prostate tissue {604, 1574,1576,1591, 2426,2807}. Several interesting candidates include AMACR, hepsin, KLF6 and EZH2. Alpha-methylacyl-CoA racemase (AMACR), an enzyme that plays an important role in bile acid biosynthesis and βoxidation of branched-chain fatty acids {748,1366} was determined to be upregulated in prostate cancer {604,1220, 1574,1575,2259,2807}. AMACR protein

expression was also determined to be upregulated in prostate cancer {604,1220, 1575,2259}. Hepsin is overexpressed in localized and metastatic prostate cancer when compared to benign prostate or benign prostatic hyperplasia {604,1574, 1591,2481}. By immunohistochemistry, hepsin was found to be highly expressed in prostatic intraepithelial neoplasia (PIN), suggesting that dysregulation of hepsin is an early event in the development of prostate cancer {604}. Kruppel-like factor 6 (KLF6) is a zinc finger is mutated in a subset of human prostate cancer {1870}. EZH2, a member of the polycomb gene family, is a transcriptional repressor known to be active early in embryogenesis {796, 1601}, showing decreased expression as cells differentiate. It has been demonstrated that EZH2 is highly over expressed in metastatic hormone refractory prostate cancer as determined by cDNA and TMA analysis {2711}. EZH2 was also seen to be overexpressed in localized prostate cancers that have a higher risk of developing biochemical recurrence following radical prostatectomy. The androgen receptor (AR) plays critical role in prostate development {2877}. It has been know for many years that withdrawal of androgens leads to a rapid decline in prostate cancer growth with significant clinical response. This response is short-lived and tumour cells reemerge, which are independent of androgen stimulation (androgen independent). Numerous mutations have been identified in the androgen receptor gene (reviewed by Gelmann {847}). It has been hypothesized that through mutation, prostate cancers can grow with significantly lower circulating levels of androgens. In addition to common mutations, the amino-terminal domain encoded by exon one demonstrates a high percentage of polymorphic CAG repeats {2638}. Shorter CAG repeat lengths have been associated with a greater risk of developing prostate cancer and prostate cancer progression {884, 2337}. Shorter CAG repeat lengths have been identified in African American men {208}. Prognosis and predictive factors The College of American Pathologists (CAP) have classified prognostic factors into three categories: Category I – Factors proven to be of prognostic importance and useful in clinical patient management.

186 Tumours of the prostate

Fig. 3.51 Prostate cancer. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. 91 families from Sweden and NA (10cM). Reprinted with permission from J.R. Smith et al. {2451}. Copyright 1996 American Association for the Advancement of Science.

Category II – Factors that have been extensively studied biologically and clinically, but whose importance remains to be validated in statistically robust studies. Category III – All other factors not suffi-

ciently studied to demonstrate their prognostic value. Factors included in category I, were preoperative PSA, histologic grade (Gleason score), TNM stage grouping,

and surgical margin status. Category II included tumour volume, histologic type and DNA ploidy. Factors in Category III included such things as perineural invasion, neuroendorcrine differentiation,

Table 3.02 Selected genes associated with prostate cancer progression.

Abbreviation GST-pi NKX3.1 PTEN

Gene Name(s)
Glutathione S-transferase pi NK3 transcription factor homolog A Phosphatase and tensin homolog (mutated in multiple advanced cancers 1) Alpha-methylacyl-CoA racemase

Locus
11q13 8p21 10q23.3

Functional Role
Caretaker gene Homeobox gene

Molecular Alteration
Hypermethlyation No mutations Mutations and haplotype insufficiency insufficiency Overexpressed in PIN/Pca Overexpressed in PIN/Pca Mutations and haplotype insufficiency Overexpressed in aggressive Pca Down regulated with Pca progression Down regulated with Pca progression

Tumour supressor gene 5p13.2-q11.1 B-oxidation of branchedchain fatty acids Transmembrane protease, serine 1 Zinc finger transcription factor Transcriptional memory

AMACR

Hepsin

Hepsin

19q11-q13.2

KLF-6

Kruppel-like factor 6/COPEB 10p15

EZH2

Enhancer of zeste homolog 2

7q35

p27

Cyclin-dependent kinase inhibitor 1B (p27, Kip1) E-cadherin

12p13

Cyclin dependent kinases 2 and 4 inhibitor Cell adhesion molecule

E-cadherin

16q22.1

________ Key: Pca=prostate cancer; PIN=prostatic intraepithelial neoplasia

Acinar adenocarcinoma 187

microvessel density, nuclear features other than ploidy, proliferation markers and a variety of molecular markers such as oncogenes and tumour suppressor genes {290}. This classification was endorsed by a subsequent World Health Organization (WHO) meeting that focused mainly on biopsy-derived factors.

A

B

Fig. 3.52 A Immunohistochemistry for AMACR protein expression in acinar adenocarcinoma of the prostate. B AMACR expression in benign prostate tissue, prostate carcinoma (PCa), hormone naive metastatic prostate cancer (hPCa), and hormone refractory metastatic prostate cancer (HR-mets).

A

B

Fig. 3.53 PSA (A) vs AMACR (B) expression in an adenocarcinoma (acinar) of the prostate. PSA is expressed in all epithelial cells of prostate origin (A) in contrast to AMACR, which is strongly expressed in the prostate cancer but not the benign epithelial cells.

Serum PSA PSA is the key factor in the screening for and detection of prostate cancer {2448}, its serum level at the time of diagnosis is considered a prognostic marker that stratifies patients into differing prognostic categories {1284,2023}. Recent reports, however indicate that the prognostic value is driven by patients with high PSA levels, which is significantly associated with increasing tumour volume and a poorer prognosis {2478}. In recent years however, most newly diagnosed patients have only modestly elevated PSA (between 2 and 9 ng/ml), a range in which BPH and other benign conditions could be the cause of the PSA elevation. For patients within this category, it was reported that PSA has no meaningful relationship to cancer volume and grade in the radical prostatectomy specimen, and a limited relationship with PSA cure rates {2478}. Following treatment, serum PSA is the major mean of monitoring patients for tumour recurrence. Stages T1a and T1b Although the risk of progression at 4 years with stage T1a cancer is low (2%), between 16% and 25% of men with untreated stage T1a prostate cancer and longer (8-10 years) follow-up have had clinically evident progression {651}. Stage T1b tumours are more heterogeneous in grade, location, and volume than are stage T2 carcinomas. Stage T1b cancers tend to be lower grade and located within the transition zone as compared with palpable cancers. The relation between tumour volume and pathologic stage also differs, in that centrally located transition zone carcinomas may grow to a large volume before reaching the edge of the gland and extending out of the prostate, whereas stage T2 tumours that begin peripherally show extraprostatic extension at relatively lower volumes {461,940,1685}. This poor correlation between volume and stage is also attributable to the lower grade in

Fig. 3.54 Expression of the Polycomb Group Protien EZH2 in prostate cancer. EZH2 demonstrates negative to weak staining in benign prostate tissue (1). Moderate EZH2 expression is seen in a subset of clinically localized PCa (2). Strong nuclear EZH2 expression is seen in the majority of hormone refractory metastatic prostate cancers (3,4).

A

B

Fig. 3.55 Expression of the Polycomb Group Protien EZH2 in prostate cancer. A Summary of EZH2 protein expression for benign prostate tissue (benign), atrophic, high-grade prostatic intraepitheial neoplasia (PIN), localized prostate cancer (PCA), and hormone refractory prostate cancer (MET). B EZH2 overexpression as determined by immunohistochemistry is significantly associated with PSA-failure following radical prostatectomy for clinically localized prostate cancer.

188 Tumours of the prostate

many stage T1b cancers. Stage T2 Most of the pathological prognostic information obtained relating to clinical stage T2 disease comes from data obtained from analysis of radical prostatectomy specimens.

Pathologic examination of the radical prostatecomy specimen The key objectives of evaluating the RP specimens are to establish tumour pathologic stage and Gleason score. It is important to paint the entire external surface of the prostate with indelible ink prior to sectioning. In most centers, the apical and bladder neck margins are removed and submitted either as shave margins en face [with any tumour in this section considered a positive surgical margin (+SM)], or preferably, these margins (especially the apical) are removed as specimens of varying width, sectioned parallel to the urethra, and submitted to examine the margins in the perpendicular plane to the ink. In this method, any tumour on ink is considered to be a +SM. The extent of sampling the radical prostatectomy specimen varies, only 12% of pathologists responding to a recent survey indicated that they processed the entire prostate {705,2283, 2645}. It was reported that a mean of 26 tissue blocks was required to submit the entire prostate and the lower portion of the seminal vesicles, {1661}. Cost and time considerations result in many centers using variable partial sampling schemes that may sacrifice sensitivity for detecting positive surgical margins (+SM) or extraprostatic extension (EPE) {2354}. Histologic grade (Gleason) Gleason score on the radical prostatectomy specimen is one of the most powerful predictors of progression following surgery. Gleason score on the needle biopsy also strongly correlates with prognosis following radiation therapy. Extraprostatic extension (EPE) This is defined as invasion of prostate cancer into adjacent periprostatic tissues. The prostate gland has no true capsule although posterolaterally, there is a layer which is more fibrous than muscular that serves as a reasonable area to denote the boundary of the prostate

{143}. At the apex and everywhere anteriorly in the gland (the latter being the fibromuscular stroma), there is no clear demarcation between the prostate and the surrounding structures. These attributes make determining EPE for tumours of primarily apical or anterior distribution difficult to establish. EPE is diagnosed based on tumour extending beyond the outer condensed smooth muscle of the prostate. When tumour extends beyond the prostate it often elicits a desmoplastic stromal reaction, such that one will not always see tumour with EPE situated in extra-prostatic adipose tissue. It has been reported that determining the extent of EPE as "focal" (only a few glands outside the prostate) and "established or non focal" (anything more than focal) is of prognostic significance {713,714}. Focal EPE is often a difficult diagnosis Modifications to this approach with emphasis on the "level" of prostate cancer distribution relevant to benign prostatic acini and within the fibrous "capsule" where it exists, has been suggested and claimed to have further value in classifying patients into prognostic categories following radical prostatectomy {2812}. More detailed analysis has not been uniformly endorsed {705}.

Fig. 3.56 Diagram depicting the pathologic stage categories of prostate cancer in the radical prostatectomy specimen: pT2: Represents an organ confined tumour with no evidence of extension to inked surgical margins, extension into extraprostatic tissue or invasion of the seminal vesicles. pT2+: Not an officially recognized category that describes an organ confined tumour with extension to inked surgical margins, but with no evidence of extension into extraprostatic tissue or invasion of the seminal vesicles. [It is important to emphasize that the status of the surgical margins while very important to document, is not a component of the TNM staging system per se as any one other pT stage categories can be associated with positive margin] pT3a: Tumour that have extended beyond the prostate into the extraprostatic tissue. [It is preferable to specify whether the amount of tumour outside the prostate is "focal" or non focal or extensive]. pT3b: Tumour invasion of the muscularis of the seminal vesicle.

Seminal vesicle invasion (SVI) Seminal vesicle invasion is defined as cancer invading into the muscular coat of the seminal vesicle {712,1944}. SVI has been shown in numerous studies to be a significant prognostic indicator {393,536,579,2589}. Three mechanisms by which prostate cancer invades the seminal vesicles were described by Ohori et al. as: (I) by extension up the ejaculatory duct complex; (II) by spread across the base of the prostate without other evidence of EPE (IIa) or by invading the seminal vesicles from the periprostatic and periseminal vesicle adipose tissue (Ib); and (III) as an isolated tumour deposit without continuity with the primary prostate cancer tumour focus. While in almost all cases, seminal vesicle invasion occurs in glands with EPE, the latter cannot be documented in a minority of these cases. Many of these patients had only minimal involvement of the seminal vesicles, or involve only the portion of the seminal vesicles that is at least partially intraprostatic. Patients in this category were reported to have a

favourable prognosis, similar to otherwise similar patients without SVI and it is controversial whether SVI without EPE should be diagnosed {712}.

Lymph nodes metastases (+LN) Pelvic lymph node metastases, when present, are associated with an almost uniformly poor prognosis in most studies. Fortunately, however, the frequency of +LN has decreased considerably over time to about 1-2% today {393,705}. Most of this decrease has resulted primarily from the widespread PSA testing and to a lesser extent from better ways to select patients for surgery preoperatively. As a consequence of this decline in patients with +LN, some have proposed that pelvic lymph node dissection is no longer necessary in appropriately selected patients {198,256}. The detection of +LN can be enhanced with special techniques such as immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR) for PSA or hK2-L
Acinar adenocarcinoma 189

A

B

Fig. 3.57 A Pathological stage and survival. Kaplan Meir plot of the level of invasion vs progression. ECE = extracapsular extension, SVI = seminal vesicle involvement, +LN = positive for lymph node metastasis.. B Kaplan Meir plot of Gleason score vs recurrence.

{659}, although these tests are not used in routine clinical practice {1948}. Various prognostic parameters based on the assessment of tumour within the node have been reported. These include Gleason grade, number of positive nodes, tumour volume, tumour diameter, DNA ploidy, and perinodal tumour extension. In part because of conflicting studies, these nodal parameters are not routinely reported in clinical practice {859, 946,1477,2372,2500}. In a rare patient, a small lymph node is seen in the periprostatic soft tissue, and may be involved by metastatic prostate cancer, even in the absence of other pelvic lymph node metastases {1364}. These patients also have a poor prognosis.

gland include stage pT2X and stage pT2+, because extraprostatic tumour at the site of the +SM cannot be excluded. Most studies suggest a lower risk of progression in men with positive margins as a reflection of capsular incision, as opposed to +SM with EPE {170, 1945,2790}. However, in a series of 1273 patients treated with radical prostatectomy, +SM had an impact on PSA non-progression rate over the spectrum of pathologic stages, including pT2 (confined) cancer. PSA non-progression rate at 5 years for patients with EPE (pT3a) with positive +SM was 50%, compared to 80% of patients with EPE and –SM (p<0.0005). A microscopically positive margin at the bladder neck should not be considered as pT4 disease {553}.

sponding radical prostatectomy specimen, there are conflicting data as to whether PNI provides independent prognostication beyond that of needle biopsy grade and serum PSA levels {180, 663,715}. It has also been demonstrated that the presence of PNI on the needle biopsy is associated with a significantly higher incidence of disease progression following radiotherapy and following radical prostatectomy {270}. As PNI is of prognostic significance and easy to assess histologically, its reporting on needle biopsy is recommended.

Surgical margin status Positive surgical margins (+SM) are generally considered to indicate that the cancer has not been completely excised and is an important prognostic parameter following surgery. Positive margins in a radical prostatectomy specimen may be classified as equivocal, focal, or extensive, with correspondingly worse prognosis {1661}. The site of the +SM is frequently at the same site as the area of EPE. However, a +SM may result from incision into an otherwise confined focus of prostate cancer. A +SM without EPE at the site of the +SM is not infrequently seen, having been reported in from 962% of cases of +SM in the literature. The most common sites of intra-prostatic incision are at the apex and at the site of the neurovascular bundle posterolaterally. Stage designations to denote a +SM in the absence of EPE anywhere in the

Perineural Invasion Perineural invasion (PNI) by prostate cancer is seen in radical prostatectomy specimens in 75-84% of cases. Due to the near ubiquitous presence of PNI in radical prostatectomy specimens and studies have not shown radical prostatectomy PNI to be an independent prognostic parameter, this finding is not routinely reported. One study has noted that the largest diameter of PNI in the radical prostatectomy was independently related to an increased likelihood of biochemical failure after radical prostatectomy; verification of this result is needed before it can be adopted in clinical practice {1641}. Numerous studies have also evaluated the significance of PNI on cancer in needle biopsy specimens. Whereas almost all reports have noted an increased risk of EPE in the corre-

Tumour volume Tumour volume can be measured most accurately with computerized planimetric methods, although a far simpler "grid" method has been described {1147}. Total tumour volume is an important predictor of prognosis and is correlated with other pathologic features. However, in several large series it was not an independent predictor of PSA progression when controlling for the other features of pathologic stage, grade and margins. These results are different from earlier series, in which many of the patients were treated in the pre-PSA era and had large tumour volumes, which resulted in a strong correlation between tumour volume and prognosis. Multiple techniques of quantifying the amount of cancer found on needle biopsy have been developed and studied, including measurement of the: 1) number of positive cores; 2) total millimeters of cancer amongst all cores; 3) percentage of each core occupied by cancer; 4) total percent of cancer in the entire specimen

190 Tumours of the prostate

{2480} Van Poppel et al. Numerous studies show associations between the number of positive cores and various prognostic variables. Biomarkers and nuclear morphometry (reviewed in {705. Extensive cancer on needle biopsy in general predicts for adverse prognosis.58 Patterns of seminal vesicle invasion (SVI).2745} Rosen et al. A majority of studies have also demonstrated that overexpression of certain other markers (p53. The other widely used method of quantifying the amount of cancer on needle biopsy is measurement of the percentage of each biopsy core and/or of the total specimen involved by cancer. but further corroboration is necessary before these tests are used Fig. and 5) fraction of positive cores.1081. only two have reported independent significance in multivariate analysis {156. {2699} Watson et al. Table 3.03 Location of positive surgical margins in radical prostatectomy specimens. a smaller number of studies analyzing large groups of patients have not found ploidy to be independently prognostically useful. {2790} Gomez et al. The differences in incidence rates amongst studies are most likely the result of the use of different criteria for the recognition of LVI. 3.Lymphovascular invasion in radical prostatectomy (LVI) The incidence rates of LVI have ranged widely from 14-53%. limited carcinoma on needle biopsy is not as predictive of a favourable prognosis due to sampling limitations. However. {2231} Epstein et al. There is no clear concensus as to superiority of one technique over the other. While most investigators do not recommend the use of immunohistochemistry for verification of an endothelial-lined space.1773}) While the preponderance of studies suggest that DNA ploidy might be useful in clinical practice. A feasible and rationale approach would be to have pathologists report the number of cores containing cancer. BCL-2.2287}. length). {2744. Number of +SM Voges et al. retraction space artefact around tumour may cause difficulty in interpretation of LVI. as well as one other system quantifying tumour extent (e. {713} Stamey et al. Although several studies have found that LVI is important in univariate analysis.g. p21WAF1) and underexpression of others (Rb) is associated with more aggressive prostate cancer behaviour. {909} 8 Apical Anterior Lateral Posterior Postero lateral Bladder neck 25 Other 37 37 - - - 27 33 18 4 11 33 - - 190 22 - - 17 14 6 - 32 69 - - - 6 - 50 34 - - - 54 - 12 90 38 11 - 26 17 9 - 22 46 - - 14 - 14 27 Acinar adenocarcinoma 191 . percentage.

Preoperative and postoperative nomograms Although there are nomograms to predict for stage prior to therapy {1284. following pathologic examination of the radical prostatectomy specimen. E-cadherin.59 Preoperative PSA levels (ng/ml) and prostatic cancer recurrence. some of these nuclear morphometry measurements are patented and under control of private companies. There are conflicting studies as to the prognostic significance of quantifying microvessel density counts. and CD44. A limitation of these nomograms is that they do not provide predictive information for the individual patient. validation Stages T3 and T4 In general. Of the patients who relapse after hormone therapy.2023}. These techniques have not become clinically accepted in the evaluation of prostate cancer since the majority of studies have come from only a few institutions. Between 50% and 60% of clinical stage T3 prostate cancers have lymph node metastases at the time of diagnosis. Numerous studies have correlated various nuclear measurements with progression following radical prostatectomy. and 75% of these patients die of prostate carcinoma within 10 years. 80% at 5 years. clinically. Distant metastases appear within 5 years in more than 85% of patients with lymph node metastases who receive no further treatment. of the several nomograms proposed in the recent times is sometimes lacking whereas comparison for superiority amongst the proposed nomograms has not always been tested.Fig. and chromogranin (neuroendocrine differentiation). Her2/neu. 3. More than 50% of patients with clinical stage T3 disease develop metastases in 5 years. The prognostic factors have appreciable limitations when they are used as stand-alone. However. Ki-67 (proliferation). In patients with distant metastases. p27kip1. the mortality is approximately 15% at 3 years. and these techniques are time consuming to perform. and 90% at 10 years. this and other prognostic factors are best assessed. many of which have been incorporated in a new postoperative nomogram {1284}. patients with clinical stage T3 prostate cancer are not candidates for radical prostatectomy and are usually treated with radiotherapy. most die within several years. 192 Tumours of the prostate .

A. De Marzo P. it appears that similar to prostate cancer. TURP specimens The incidence of HGPIN in transurethral resection of the prostate is relatively uncommon with two studies reporting a rate of 2.. – Histological transition from HGPIN to cancer has been described {1687}. Helpap Definition Prostatic intraepithelial neoplasia (PIN) is best characterized as a neoplastic transformation of the lining epithelium of prostatic ducts and acini.1996}. In an autopsy series of 180 African and White-Brazilian men older than 40.e. In 48 men who underwent cystoprostatectomy for reasons other than prostate cancer.1926. severity and extent of HGPIN in prostate with cancer {1683.Prostatic intraepithelial neoplasia W. – The extent of sampling (i. 26.2122. In a contemporary autopsy series of 652 prostates with high proportion of young men. Investigators have found HGPIN in 85100% of radical prostatectomy specimens {568. 49. Montironi J. respectively.2125. – Both HGPIN and cancer are multifocal with a predominant peripheral zone distribution {2122}. identified HGPIN in 7. 2434}. The European and the Japanese literature indicate a slightly lower prevalence of HGPIN on needle biopsies {58.A. Sakr et al. By definition.60 Focal high grade PIN (upper and lower right) in otherwise normal prostatic gland.M. extent of screening/early detection activities). – Observers variability as there is an inherent degree of subjectivity in applying diagnostic criteria and in setting the threshold for establishing diagnosis.594.A. this process is confined within the epithelium therefore. 3.1435. HGPIN can be detected microscopically in young males. Troncoso et al. section thickness and staining quality). 46. Sakr R. 1133. This is likely to result from several reasons: – Population studied (ethnicity. have reported a prevalence of 4-6% {296.2824}. Based on few recent autopsy studies that included HGPIN in their analysis. HGPIN in radical prostatectomy/ cystoprostatectomy specimens The prevalence of HGPIN in radical prostatectomy specimens is remarkably high reflecting the strong association between the lesion and prostate cancer. 29. In addition to higher the prevalence.2046.572. respectively {2644}. – There is an increased frequency. Morphological relationship of HGPIN to prostate carcinoma The associations of HGPIN and prostate cancer are several {1776}: – The incidence and extent of both lesions increase with patient age {2280}.2830}. found 49% and 61% of the prostates to harbour HGPIN and carcinoma. The majority of large recent series. Humphrey B. this study also suggested a more extensive HGPIN in younger African American men compared to Caucasians {2279}. – The technical quality of the material evaluated (fixation. Wiley et al. intraepithelial. 53 and 67% for Caucasian men {2278}. ICD-O code 8148/2 Epidemiology There is limited literature characterizing the epidemiology of high grade prostatic intraepithelial neoplasia (HGPIN) as the lesion has been well defined relatively recently with respect to diagnostic criteria and terminology. 75 and 91% of African Americans between the third and eighth decades compared to: 8. respectively {845. number of core biopsies obtained).2122.2279. More extensive HGPIN predicted significantly for the presence of prostate cancer in this study {2824}. .1913. – High-grade PIN shares molecular Prostatic intraepithelial neoplasia 193 Fig.I.1993.2644}.1993}. Rubin A. Epstein M. its prevalence increases with age and HGPIN shows strong association with cancer in terms of coincidence in the same gland and in its spatial distribution {1683. 23. 72. more extensive and diffuse HGPIN in African Brazilians tended to appear at a younger age compared to Whites {244}. In a series of 100 cystoprostatectomy specimens. Prevalence of HGPIN in surgical prostate samples Biopsy specimens There are significant variations in the reported prevalence of HGPIN in needle biopsies of the prostate.3% and 2. {2046} found 83% and 46% of the prostates to contain HGPIN and incidental carcinoma.8%.

1777. The distinction between low and high grade PIN is based on the degree of architectural complexity and more importantly. HGPIN by itself does not appear to elevate serum PSA levels {57. Subsequently. on the extent of cytologic abnormalities.2144. In low grade PIN. 2281}.1777. Higher magnification. There is limited data addressing the relationship between the presence and extent of HGPIN in the prostate and the pathologic stage of prostate cancer. Clinical features HGPIN does not result in any abnormalities on digital rectal examination. usually inconspicuous nucleoli while a few may contain more prominent nucleoli. 3. It has been reported that the total volume of HGPIN increases with increasing pathologic stage with a significant correlation between volume of HGPIN and the number of lymph node metastases {2122}. genetics features with cancer {2121}. PIN was divided into three grades based on architectural and cytologic features recognizing that the changes cover a continuum. 3. 2227}.A B Fig.2281}. there is proliferation and "piling up" of secretory cells of the lining epithelium with irregular spacing. inactivation of tumour suppressor genes or overexpression of oncogenes {721.2007.61 A Flat and tufting pattern of growth of high grade PIN. HGPIN is more strongly associated with intermediate-high grade prostatic carcinoma {708.995.2122. Expanded duct with micropapillary proliferation of enlarged secretory epithelial cells with high nuclear cytoplasmic ratio and enlarged nucleoli. manifesting as a hypoechoic lesion on transrectal ultrasound examination {1012}. expression profile that is more closely related to prostate cancer than to benign prostatic epithelium.62 A Low grade PIN.2121. B Low grade PIN.721. B 194 Tumours of the prostate . These studies investigated aspects ranging from cell proliferation and death.2007. Molecular genetic associations of HGPIN and prostate cancer There is extensive literature indicating that HGPIN demonstrates a range of genetic abnormalities and biomarker Histopathology Initially. histomorphometric analysis and a host of genetic alterations. B High grade PIN. The basal cell layer A Fig. HGPIN may appear indistinguishable from cancer. Some nuclei have small. it has been recommended that the classification should be simplified into a two-tier system: low (previous grade I) and high (previous grades II and III) grade lesions {638}.

invasive signet-ring carcinoma. In high grade PIN. signet ring type. as demonstrated by positive basal cell staining (34BE12 immunostain). the acini and ducts are lined by malignant cells with a variety of architectural complexity and patterns. The individual cells are almost uniformly enlarged with increased nuclear/cytoplasmic ratio. Histologically. It is difficult to reproducibly distinguish low grade PIN from normal and hyperplastic epithelium {709}. The vacuoles are mucin-negative by histochemical staining (mucicarmine. of mucinous type. cytoplasmic vacuoles displace and indent PIN cell nuclei. nuclei towards the centre of the gland tend to have blander cytology. and cribrifrom: nuclear atypia without significant architectural changes (flat pattern). Cytologically. B High-grade prostatic intraepithelial neoplasia.A B Fig. nuclei become more piled up. In all cases signet-ring cell PIN was admixed with adjacent. Intraluminal signet ring neoplastic cells confined to a pre-existing gland. High grade prostatic intraepithelial neoplasia (PIN) with signet-ring cells is exceedingly rare with only three reported cases {2181}. which are flat. with a flat pattern of growth. micropapillary. more complex architectural patterns appear such as Roman bridge and cribriform formation (cribriform pattern). B Cribriform high grade PIN. High grade PIN is characterized by a more uniform morphologic alteration.64 A High-grade prostatic intraepithelial neoplasia. The grade of PIN is assigned based on assessment of the nuclei located up against the basement membrane. resulting in undulating mounds of cells (tufting pattern). Architectural patterns of HGPIN Four patterns of HGPIN have been described. columns of atypical epithelium that typically lack fibrovascular cores (micropapillary pattern). Note intraluminal filling of the gland by blue mucin. 3. Histologic variants Signet-ring variant. Note more benign appearing cytology towards center of gland. as compared to peripherally located nuclei. Prostatic intraepithelial neoplasia 195 . The distinction between cribriform high grade PIN and ductal carcinoma in-situ is controversial (see duct carcinoma in-situ) {288}. A B Fig. therefore showing less variation in nuclear size than that seen in low grade PIN. 3. Alcian blue. normally rimming ducts and acini is intact in low grade PIN. PAS). Many cells of HGPIN contain prominent nucleoli and most show coarse clumping of the chromatin that is often present along the nuclear membrane. HGPIN can be readily appreciated at low power microscopic examination by virtue of the darker "blue" staining of the lining that reflects the expanded nuclear chromatin area {294}.63 A Micropapillary high grade PIN. Note more benign appearing cytology towards center of gland. tufting.

Mucinous high grade PIN exhibits solid intraluminal masses of blue tinged mucin that fill and distend the PIN glands.65 High grade PIN with foamy cytoplasmic features. resulting in a flat pattern of growth. Small neoplastic cells. glandular-type PIN cells. Two cases of foamy gland high-grade PIN have been published {223}. invasive. typical acinar adenocarcinoma (of Gleason score 5-7). Inverted variant. The inverted. with rosette-like formations. which display peripheral. but no associated invasive foamy gland adenocarcinoma. there was associated usual. with papillary infoldings lined by cells with bland nuclei and xanthomatous cytoplasm. Extremely rare examples with small cell neuroendocrine cells exist {2181. B Inverted high grade PIN. The frequency was estimated to be less than 1% of all PIN cases. A B Fig. neurosecretory granules at the ultrastructural level. The small neoplastic cells are chromogranin and synaptophysin-positive. A Tufted growth pattern. variant is typified by polarization of enlarged secretory cell nuclei toward the glandular lumen of high-grade PIN glands with tufted or micropapillary architectural patterns. This is a rare pattern.A B Fig. small acinar Gleason score 6-7 adenocarcinoma {111}. Mucinous variant. The most salient morphologic feature distin- Fig. foamy PIN glands are large. which are surrounded by basal cells. Foamy variant. It is associated with adjacent. invasive mixed small celladenocarcinoma. Microscopically. with five reported cases.1689. 3. Small cell neuroendocrine variant.67 Small cell neuroendocrine high-grade prostatic intraepithelial neoplasia. or hobnail. In one case there was admixed. 2256}. are observed in the centre of glands. 3. In six of 15 reported needle biopsy cases. and harbour densecore. The nuclei are polarized towards the luminal aspect of the gland.2474}. Intraductal carcinoma is controversial as it has overlapping features with cribriform high grade PIN and can not be separated from intraductal spread of adenocarcinoma of the prostate {479. B Higher magnification demonstrates foamy cytoplasmic features. In one case there was extensive associated Gleason grade 3+3=6 acinar adenocarcinoma.66 A Inverted pattern of high grade prostatic intraepithelial neoplasia. 196 Tumours of the prostate . membrane-bound. 3. but not mucinous adenocarcinoma {2181}. All three entities consist of neoplastic cells spanning prostatic glands.

which is usually found to be similar to. gens. GSTP1 is hypermethylated in approximately 70% of HGPIN lesions {325}. Many other genes have been shown to be overexpressed in PIN as compared to normal epithelium {295}. inhibitors of which may be selectively toxic to prostate cancer cells. while low-grade PIN is not.569. paralleling that seen in carcinoma {17. Other fairly common numeric changes include gains of chromosomes 10.1398. In comparison. Somatic genetics Germ-line heritable alterations There is no evidence that the frequency or extent of high grade PIN is increased in patients with familial prostate cancer {181}. Other experts will use the term "intraductal carcinoma" on biopsy with the recognition that definitive therapy may be undertaken. have been reported to be very common in high grade PIN {694}.1220. The BCL-2 protein is present in at least a subset of high grade PIN lesions {271}. Other regions of loss in both prostate cancer and PIN include chro- Specific genes involved in the pathogenesis of PIN There is decreased protein expression in HGPIN of NKX3. which is known to inactivate carcino- . 752.1926}. has been seen to be consistently overexpressed in prostate cancer and high grade PIN {2401.A B Fig. Loss of regions of chromosome 8p. Telomerase activity has been reported to occur in 16% of high grade PIN lesions {1344} and 85% of invasive prostatic carcinomas {2461} and may serve as an important biomarker in prostate carcinogenesis.1588. and usually lower than metastatic disease. recognizing that infiltrating cancer will be identified upon further prostatic sampling {719}.68 A Ductal carcinoma in-situ with typical cribrifrom pattern on growth. or somewhat lower than. CMYC may be over-represented at times and PSCA is overexpressed in some lesions at the mRNA level {2165}. High-grade PIN with adjacent atypical glands seems to confer a higher risk for subsequent diagnosis of carcinoma compared to high-grade PIN alone. B Ductal carcinoma in-situ with necrosis demonstrating retention of basal cell layer as revealed by high molecular weight cytokeratin staining. TP53 mutations and protein overexpression may be identified in at least some PIN lesions {48.2333}. 12.2259.1293}. in most studies. The mean incidence of carcinoma detection on rebiopsy after a diagnosis of high-grade PIN in needle biopsy tissue is about 30% {559. as evidenced by telomere shortening {204. gives rise to prostate cells with an increased burden of DNA adducts and hence mutations {1879}. Frequent changes in PIN include both increases and decreases in chromosome 8 centromeric region. at times there are foci of PIN with more anomalies than nearby carcinoma {2120}.2546}.1214. 16q and 18q. averProstatic intraepithelial neoplasia 197 Somatic genomic alterations Genetic changes tend to be very similar to the chromosomal aberrations identified in prostatic adenocarcinoma {204. The large majority (80-90%) of cases of carcinoma are detected on the first re-biopsy after a high-grade PIN diagnosis {1398}.2120}. In practice.2856}.1520. Fatty acid synthetase (FAS).1696. and Y. the rebiopsy cancer detection frequency is about 20% after a diagnosis of benign prostatic tissue {715.1698}.2823} with a strong recommendation for repeat biopsy. invasive carcinoma. high grade PIN shares with invasive cancer some degree of chromosomal instability. Re-biopsy may also detect persistent high-grade PIN in 5-43% of cases {559. 1398. 7. mosomes 10q. as is known for prostate cancer {276}.1926}. AMACR is also increased in at least a subset of high grade PIN lesions {604.1399. GSTP1.304. this process may rarely be present without small glands of adenocarcinoma.1 and p27.2873}. 3. where some experts consider it prudent to refer to the lesion as high grade cribriform PIN {2256. guishing "intraductal carcinoma" from high-grade cribriform PIN is the presence of multiple cribriform glands with prominent cytological atypia containing comedo necrosis. a risk factor for the subsequent detection of carcinoma. Prognosis and predictive factors Needle biopsy High-grade PIN in needle biopsy tissue is. and 16% after a diagnosis of low-grade PIN. The overall incidence of any aneuploidy in high grade PIN using FISH is approximately 50-70%.15741576. In prostate needle biopsies and TURP. this distinction rarely poses a problem in the evaluation of a prostatectomy specimen as invasive cancer is always concurrently present.237. often with simultaneous loss of regions from 8p and gains of 8q. While many of the acquired chromosome aberrations in PIN do not appear random. While carcinoma foci generally contain more anomalies than paired PIN foci.

1996}.1926}. Due to the magnitude of the risk. However. all men with this finding should undergo re-biopsy {1399}. ties and/or immunophenotype of highgrade PIN are not currently utilized to stratify risk for subsequent detection of carcinoma.04 Risk of subsequent carcinoma detection after rebiopsy. this recommendation may change with emerging data indicating a lower risk of prostate carcinoma following a needle biopsy showing HGPIN. whereas a long-term study from Norway demonstrated no association between the presence of high grade PIN on TURP and the incidence of subsequent cancer {1034}. PINATYP: high grade PIN with adjacent small atypical glands. with a mean Gleason score of 6 (range 5-7) {1294}. Current standards of care recommend that patients with isolated high-grade PIN be re-biopsied in 0-6 months.aging 53% {70. It is not settled whether serum PSA and digital rectal examination findings provide further information beyond PIN presence on risk for subsequent detection of carcinoma {995. 198 Tumours of the prostate .1399. Radical prostatectomy specimens removed for carcinoma detected after a diagnosis of high-grade PIN contain mostly organ-confined cancer.1398}. Treatment is currently not indicated after a needle biopsy diagnosis of high-grade PIN {994}.2386}. Patients with isolated highgrade PIN in needle biopsy may be considered for enrollment into clinical trials with chemoprevention agents {1929.2010}. it may be recommended that needle biopsies be performed to rule out a peripheral zone cancer. since high-grade PIN is a general risk factor for carcinoma throughout the gland. When high grade PIN is found on TURP. In an older man without elevated serum PSA levels. For example. There are inconsistent data as to whether the extent of HGPIN and its architectural pattern predict risk of subsequent carcinoma {559. Genetic abnormaliTable 3.1435. some pathologists recommend sectioning deeper into the corresponding block and most pathologists recommend processing the entire specimen {1996}. irrespective of the serum PSA level and DRE findings.1294. In a younger man with high grade PIN on TURP. in one study fully 35% of carcinomas would have been missed if only the side with the highgrade PIN had been re-biopsied {2386}. TURP Several studies have found that high grade PIN on TURP places an individual at higher risk for the subsequent detection of cancer {845.1398. clinical follow-up is probably sufficient. Needle biopsy diagnosis Percentage of patients with carcinoma on rebiopsy 20% Benign prostatic tissue High grade PIN PINATYP2 1 2 30% 53% PIN: prostatic intraepithelial neoplasia. The rebiopsy technique should entail at least systematic sextant re-biopsy of the entire gland {277. 2278}.

938}. Methods of diagnosis Serum PSA levels may be normal particularly in a patient with only centrally located tumour. they are associated with variable serum PSA levels {323}. Ductal adenocarcinoma 199 . ICD-O code 8500/3 Synonyms Several terms used in the past are no longer appropriate. In most cases. Clinical features Signs and symptoms Periurethral or centrally located ductal adenocarcinoma may cause haematuria.2919}.69 Ductal adenocarcinoma of the prostate.1707}. histochemistry and immunohistochemistry have proven the prostatic origin of this tumour {1990. subsequent studies on favourable response to orchiectomy. Although ductal adenocarcinoma strongly expresses prostate specific antigen (PSA) immunohistochemically. transurethral resections performed for diagnosis or relief of the urinary obstruction will provide sufficient diagnostic tis- A B Fig. A Papillary type of growth. Yang L. Both centrally and peripherally located ductal adenocarcinoma components can be present in the same prostate. Helpap H. because it could also refer to urothelial carcinoma involving prostatic ducts. Epidemiology In pure form. Cheng B.2-0.718. A centrally located adenocarcinoma may also be associated with a peripherally located acinar adenocarcinoma. urinary urgency and eventually urinary retention. there may be no abnormalities on rectal examination. Prostatic duct carcinoma should be used with caution. Tumours arising peripherally may lead to enlargement or induration of the prostate. More commonly it is seen with an acinar component. Endometrial carcinoma was originally used to describe this entity because of its morphologic similarity to endometrium. However.2888.Ductal adenocarcinoma X. Etiology No specific etiologic factors have been defined for this particular type.J. Samaratunga Definition Subtype of adenocarcinoma composed of large glands lined by tall pseudostratified columnar cells. In these cases. Localization Ductal adenocarcinoma may be located centrally around the prostatic urethra or more frequently located peripherally admixed with typical acinar adenocarcinoma. ultrastructural studies. B Cribriform pattern. 3.8% of prostate cancers {292. ductal adenocarcinoma accounts for 0. the term endometrial or endometrioid carcinoma should not be used.2205. This tumour was previously believed to be derived from a Müllerian structure named prostatic utricle {1706. Therefore.

70 Ductal adenocarcinoma. 2654}. which makes a diagnosis difficult particularly on needle biopsy. The cytoplasm of ductal adenocarcinoma is often amphophilic and may occasionally appear clear. the cytological atypia is minimal. ductal adenocarcinomas appear to have a tendency to metastasize to lung and penis {491. Macroscopy/Urethroscopy Centrally occurring tumours appear as exophytic polypoid or papillary masses protruding into the urethra around the verumontanum. Transrectal needle core biopsies may also obtain diagnostic tissue when the tumour is more peripherally located {323}. glandular or solid patterns as seen in acinar adenocarcinoma. The metastasis of ductal adenocarcinoma may show pure ductal. In addition. which form a single or pseudostratified layer reminiscent of endometrial carcinoma. which are often intermingled {286. 3. Tumour spread and staging Ductal adenocarcinoma usually spread along the urethra or into the prostatic ducts with or without stromal invasion. A B Fig. Histopathology Ductal adenocarcinoma is characterized by tall columnar cells with abundant usually amphophilic cytoplasm. Ductal adenocarcinoma displays a variety of architectural patterns. there are numerous mitoses and marked cytological atypia. However. areas of ductal adenocarcinoma may be incidentally identified in prostatectomy specimens. acinar or mixed components. they are mostly equivalent to Gleason patterns 4. Fig. Peripherally occurring tumours typically show a white-grey firm appearance similar to acinar adenocarcinoma. In contrast to ordinary acinar adenocarcinoma. In other cases. Peripherally located tumours are often admixed with cribriform. Other patterns of spread are similar to that of acinar prostatic adenocarcinoma with invasion to extraprostatic tissues and metastasis to pelvic lymph nodes or distal organs. In some cases comedo necrosis is present whereby they could be considered equivalent to Gleason pattern 5. 3. some ductal adenocarcinomas are associated with a prominent fibrotic response often including haemosiderin-laden macrophages. B High magnification shows tall pseudostratified arrangement of nuclei diagnosed as ductal adenocarcinoma despite bland cytology. Although ductal adenocarcinomas are not typically graded. Infiltrating cribriform and pepillary growth pattern. In some cases.71 A Mixed cribriform acinar and papillary ductal adenocarcinoma. 200 Tumours of the prostate .sue.720}.

Immunoprofile Immunohistochemically ductal adenocarcinoma is strongly positive for PSA and PAP. Solid pattern can only be identified when it is associated with other patterns of ductal adenocarcinoma. however. resembling colonic adenocarcinoma.Papillary pattern can be seen in both centrally or peripherally located tumours. Ductal adenocarcinoma 201 .72 A Separate acinar (left) and ductal adenocarcinoma (right). C Ductal adenocarcinoma of the prostate showing close morphologic resemblance to endometrial carcinoma. Some patterns of ductal adenocarcinoma may represent ductal carcinoma in situ. benign prostatic polyps. B Individual glands of prostatic duct adenocarcinoma. yet is more common in the former.2205}. and proliferative papillary urethritis. Ductal adenocarcinoma must be distinguished from urothelial carcinoma. ectopic prostatic tissue. Some reported that 25-40% of cases had metastases at the time of diagnosis with a poor 5-year survival rate ranging from 15-43% {462. One of the more difficult differential diagnoses is cribriform high grade prostatic intraepithelial neoplasia. It is not known whether prognosis correlates with the degree of cytological atypia or growth patterns. Androgen deprivation therapy may provide palliative relief. 3. The cribriform pattern is formed by back-to-back large glands with intraglandular bridging resulting in the formation of slit-like lumens. Cribriform pattern is more commonly seen in peripherally located tumours. Even limited ductal adenocarcinoma on biopsy warrants definitive therapy. Prognosis and predictive factors Most studies have demonstrated that ductal adenocarcinoma is aggressive. Individual gland pattern is characterized by single glands. although they may be also present in centrally located tumours. A B C Fig. The solid nests of tumour cells are separated by incomplete fibrovascular cores or thin septae.718. Tumour cells are typically negative for basal cell specific high molecular weight cytokeratin (detected by 34βE12). even though these cancers are less hormonally responsive than acinar adenocarcinoma. preexisting ducts may be positive for this marker.

899.8% of prostatic tumours in adults {942. In some cases patients present with signs and symptoms related to metastases {2159}.943}. With extensive tumour involvement. squamous or glandular differentiation can be seen. 1907.1278. Localization Primary urothelial carcinoma is usually located within the proximal prostatic ducts. In one series 4 of 6 patients had elevated serum PSA (>4 ng/ml) in the absence of prostatic adenocarcinoma {1951}. ICD-O code 8120/3 involving the Epidemiology The frequency of primary urothelial carcinoma ranges from 0. Methods of diagnosis Most cases are diagnosed by transurethral resection or less often needle biopsy {1951}. Angiolymphatic invasion is often identified.J. In all suspected cases the possibility of secondary involvement from a bladder primary must be excluded. there is a T1 category for invasion of subepithelial connective tissue distinct from invasion of prostatic stroma (T2). It has been postulated that this may arise through a hyperplasia to dysplasia sequence. deeply invasive urothelial carcinoma from the bladder directly invades the prostate. cords and single cells.2837}.73 Urothelial carcinoma invading prostate.2673}. A few examples of papillary urothelial neoplasms arising within prostatic ducts are described {1278}. The vast majority.Urothelial carcinoma D. Less commonly. frequent mitoses and apoptotic bodies. These tumours are staged as urethral tumours {944}. Secondary urothelial carcinoma of the prostate is usually accompanied by CIS of the prostatic urethra {2673}. The prognostic importance of these categories has been confirmed in clinical studies {442}. Histopathology The full range of histologic types and grades of urothelial neoplasia can be seen in primary and secondary urothelial neoplasms of the prostate {442}. With stromal invasive tumours. Metastases are to regional lymph nodes and bone {2556}. Digital rectal examination is abnormal in the majority but is infrequently the presenting sign {1951}. Subsequent spread is by invasion of prostatic stroma.7-2.2159}. Incidental adenocarcinoma of the prostate is found in up to 40% of cystoprostatectomy specimens removed for urothelial carcinoma of the bladder and can accompany primary urothelial carcinoma {1772}.1231}. This is highest when there is multifocality or carcinoma in situ associated with the invasive carcinoma {1907}. The in situ component has the characteristic histologic features of urothelial carcinoma in situ elsewhere with marked nuclear pleomorphism. Many cases are locally advanced at diagnosis and extensively replace the prostate gland. Stromal invasion is associated with a prominent desmoplastic stromal response with tumour cells arranged in small irregular nests. Clinical features Signs and symptoms Primary urothelial carcinoma presents in a similar fashion to other prostatic mass- es including urinary obstruction and haematuria {943. Bone metastases are osteolytic.1893.2445. urothelial carcinoma fills and expands ducts and often develops central comedonecrosis. Most patients are older with a similar age distribution to urothelial carcinoma of the bladder (range 45-90 years) {942. a common prob- 202 Tumours of the prostate . Grignon Definition Urothelial carcinoma prostate. For tumours involving the prostatic ducts. In patients with invasive bladder carcinoma. the bladder tumour can be occult and random biopsies may be necessary to exclude this possibility {2313. Tumour spread and staging In situ carcinoma can spread along ducts and involve acini. Biopsies of the prostatic urethra and suburethral prostate tissue are often recommended as a staging procedure to detect secondary urothelial cancer involving the prostate of patients undergoing conservative treatment for superficial bladder tumours.1951. Fig. Local spread beyond the confines of the prostate may occur. since in the majority of cases the more centrally located prostatic ducts are involved by urothelial neoplasia to a greater extent than the peripheral ducts and acini. are high-grade and are associated with an in situ component {442. Involvement of the prostate appears to be by direct extension from the overlying urethra. or the tumour can spread along ejaculatory ducts and into seminal vesicles.2905}. A single cell pattern of pagetoid spread or burrowing of tumour cells between the basal cell and secretory cell layers of the prostate is characteristic. there is involvement of the prostate gland in up to 45% of cases {1596.2580}. possibly from reserve cells within the urothelium {696. There is limited data on PSA levels in patients with urothelial carcinoma of the prostate. however. 3. Inflammation in the adjacent stroma frequently accompanies in situ disease but without desmoplasia. Etiology Primary urothelial carcinomas presumably arise from the urothelial lining of the prostatic urethra and the proximal portions of prostatic ducts. In cases of direct invasion of the prostate from a poorly differentiated urothelial carcinoma of the bladder.

lem is its distinction from a poorly differentiated prostatic adenocarcinoma. A B Fig. B Tumour cells are negative for PSA immunostaining. Urothelial cancer tends to grow in nests.75 A Urothelial carcinoma extensively involving prostatic ducts. B Pagetoid spread of tumour cells between the basal cell and secretory cell layers. B Infiltrating high grade urothelial carcinoma (left) with more pleomorphism than adenocarcinoma of the prostate. in contrast to the foamy.A B Fig.74 A Inflammation without desmoplasia accompanying in situ carcinoma. A B Fig. 3. Poorly differentiated urothelial carcinomas have greater pleomorphism and mitotic activity compared to poorly differentiated adenocarcinomas of the prostate. 3. Urothelial carcinomas tend to have hard glassy eosinophilic cytoplasm or more prominent squamous differentiation. pale cytoplasm of prostate adenocarcinoma. Urothelial carcinoma 203 .76 A Infiltrating high grade urothelial carcinoma with scattered cells showing squamous differentiation. 3. whereas the adjacent prostatic gland epithelium expresses PSA.

77 A Urothelial carcinoma (lower left) and adenocarcinoma of the prostate (upper right). Residual basal cells are frequent in the in situ areas {440}.8 months (range 1 to 93 months) {899}. In 10 cases of primary urothelial carcinoma reported by Goebbels et al. survival was 100% for patients with noninvasive disease treated by radical cystoprostatectomy {442}. 3.78 34betaE12 expressing residual basal cells delineate in situ areas of urothelial carcinoma. Immunoprofile The tumour cells are negative for PSA and PAP {440. which are negative in prostate adenocarcinoma. In one series.CK20 in the majority of cases and high molecular weight cytokeratin or P63 in about 50% of cases {1951}. Tumour cells express CK7 and 204 Tumours of the prostate . However. patients usually will be recommended for radical cystoprostatectomy as intravesical therapy is in general not thought to be effective in treating prostatic involvement. In one series. a finding that should not be misinterpreted as positive staining. A B C Fig. 3. as opposed to cords of cells or focal cribriform glandular differentiation typical of prostatic adenocarcinoma. mean survival was 28. Prostatic secretions in the ductal lumens can react positively resulting in faint staining of tumour cells at the luminal surface. even if only intraductal urothelial carcinoma is identified on TURP or transurethral biopsy in a patient followed for superficial bladder cancer.442. overall survival was 45% at 5 years in 19 patients with stromal invasion {442}. B Urothelial carcinoma in situ extending into large periurethral prostatic duct. Fig. C Urothelial carcinoma in situ with involvement of prostatic epithelium with undermining and pagetoid spread.1951}. With stromal invasion or extension beyond the confines of the prostate prognosis is poor {261.1437}. Prognosis and predictive factors For patients with either primary or secondary urothelial carcinoma of the prostate the single most important prognostic parameter is the presence of prostatic stromal invasion.943. Urothelial cancers may also express thrombomodulin and uroplakins.

A proportion of cases show an initial response to hormone therapy {32. Hormone treatment and chemotherapy are not effective. it does not express PSA or PAP {1861.1176}. requiring transurethral resection {179}. Localization Squamous cell carcinomas may originate either in the periurethral glands or in the prostatic glandular acini. There are 70 cases reported in literature. Patients may also present with metastatic disease. 3. For primary prostatic squamous cell carcinoma an association with Schistosomiasis infection has been described {44}. including total urethrectomy is recommended {1513}. Some authors considered the possibility that adenosquamous carcinomas consist of collision tumours with a de novo origin of adenocarcinoma and squamous cell carcinoma {841}.6% of all prostate cancers {1814. Histologically. whereas the squamous component displays high molecular weight cytokeratins {179}.2613}. Clinical features Most.H. squamous cell carcinoma must be distinguished from squamous metaplasia as may occur in infarction or after hormonal therapy. and bone metastases are osteolytic. Histopathology By definition pure squamous cell carcinoma does not contain glandular features and it is identical to squamous cell carcinoma of other origin. probably from the lining basal cells. Adenosquamous carcinomas are probably localized more commonly in the transition zone of the prostate accounting for their more frequent detection in transurethral resection specimens {179. Adenosquamous carcinoma is defined by the presence of both glandular (acinar) and squamous cell carcinoma components. radical prostatectomy or cystoprostatectomy.931}. with about 10 cases reported so far. Primary prostatic squamous cell carcinoma must be distinguished on clinical grounds from secondary involvement of the gland by bladder or urethral squamous carcinoma. The age range of patients is between 52 and 79 years {1861}. except for a single case with non-progressive disease after local irradiation and systemic chemotherapy {2657}. B Squamous cell carcinoma of the prostate with focal keratinization. Adenosquamous carcinomas may be detected by increased serum PSA. Even more rare is adenosquamous carcinoma of the prostate. which show a divergent differentiation pathway {606. Tumour spread Both squamous cell carcinomas and adenosquamous carcinomas tend to metastasize rapidly with a predilection for the skeletal bones {841. occasionally in association with bone pain and haematuria. Approximately 50% of adenosquamous carcinomas may arise in prostate cancer patients subsequent to endocrine therapy or radiotherapy {179}. Van der Kwast Definition Tumours with squamous cell differentiation involving the prostate. PSA levels are not typically elevated. Most patients have at the time of diagnosis metastatic disease.Squamous neoplasms T.79 A Cross section of squamous cell carcinoma.2657}. With rare exception. . In cases of organ-confined disease.1861}.1861}. The glandular tumour component generally expresses PSA and PAP. but more typically by obstruction of the urinary outflow. if not all pure squamous cell carcinomas become clinically manifest by local symptoms such as urinary outflow obstruction. ICD-O codes Adenosquamous carcinoma Squamous cell carcinoma 8560/3 8070/3 Epidemiology The incidence of squamous cell carcinoma of the prostate is less than 0. A B Squamous neoplasms 205 Fig.

Basal cell carcinoma P. which can give rise to a spectrum of proliferative lesions ranging from basal cell hyperplasia to basal cell carcinoma {271. It is believed that a subset of basal cells are prostatic epithelial stem cells. presenting with urinary obstruction with TURP being the most common tissue source of diagnosis. necrosis and stromal desmoplasia. although it should be considered as florid nodular basal cell hyperplasia.80 Basal cell carcinoma resembling basal cell hyperplasia. raising the possibility of myoepithelial differentiation. along with dis- tant metastases {597. basal cell carcinoma shows strong BCL2 positivity and high Ki-67 indices as compared to basal cell hyperplasia {2868}.2893}. Distinction from basal cell hyperplasia with a pseudoinfiltrative pattern or prominent nucleoli can be difficult. S-100 staining is described as weak to intensely positive in about 50% of tumour cells {954.H. extraprostatic extension. The youngest reported case was 28 years old {597}. confirming its relationship with prostatic basal cells.2410}.1160}. A benign morphologic counterpart to basal cell carcinoma (basal cell adenoma) has been proposed. Other patterns have histologic similarity to florid basal cell hyperplasia or the adenoid basal cell pattern of basal cell hyperplasia (the latter pattern of cancer occasionally referred to as adenoid cystic carcinoma). 3. C Perineural invasion. Local extra-prostatic extension may be seen. Fig. but there is no corroborative antismooth muscle actin (HHF35) reactivity {954} nor ultrastructural evidence of a myoepithelial nature {2893}.1139. Tan A. Prognosis The biologic behaviour and treatment of basal cell carcinoma is not well elucidated in view of the few cases with mostly short follow-up. perineural invasion.2007. B Basal cell carcinoma resembling adenoid cystic carcinoma. Histologic criteria for malignancy that distinguish it from basal cell hyperplasia include an infiltrative pattern. 3. Basal cell carcinoma shows immunoreactivity for keratin 34βE12. Histopathology Some tumours resemble its namesake in the skin. ICD-O code 8147/3 Clinical features Patients are generally elderly. Billis Definition This is a neoplasm composed of prostatic basal cells. comprising large basaloid nests with peripheral palisading and necrosis. 206 Tumours of the prostate . A B C Fig.81 Basal cell carcinoma A Note central comedonecrosis.

which meets the diagnostic criteria for carcinoid tumour elsewhere are exceedingly rare {609.478.Neuroendocrine tumours P. or in a more diffuse pattern {1178} and receptors for serotonin {16} and neuroendocrine peptides {1017.384. 3. They should be essentially negative for PSA.2802}.2537} may also be present. 1395.I. particularly in PSA negative.1222. Carcinoid tumour (WHO well differentiated neuroendocrine tumour) and 3. In 5-10% of prostatic carcinomas there are zones with a large number of single or clustered neuroendocrine cells detected by chromogranin A immunostaining {29. Immunostaining for neuron-specific enolase.H. Helpap P.A.A.1822. androgen independent carcinomas {227.1915. Basal cell carcoma / Neuroendocrine tumours 207 . 3. Serum chromogranin A levels (and potentially other markers such as pro-gastin-releasing peptide) {2537. Small cell neuroendocrine carcinoma (new WHO classification poorly differentiated neuroendocrine carcinoma) ICD-O codes Focal neuroendocrine differentiation in prostatic adenocarcinoma 8574/3 Carcinoid 8240/3 Small cell carcinoma 8041/3 Focal neuroendocrine differentiation in prostatic adenocarcinoma All prostate cancers show focal neuroendocrine differentiation. Epstein B. Focal neuroendocrine differentiation in conventional prostatic adenocarcinoma 2. Humphrey R.82 A.2582}. The definitional context of these other neuroendocrine elements (other than chromogranin A and serotonin) remains to be elucidated.1066}. focal neuroendocrine differentiation portends a poor prognosis {446. 2918}.31.2317. There are conflicting studies as to whether advanced androgen deprived and androgen independent carcinomas show increased neuroendocrine differentiation {446. B Adenocarcinoma with fine eosinophilic granules indicating neuroendocrine differentiation. Carcinoid tumours True carcinoid tumours of the prostate. Vascular endothelial growth factor (VEGF) may also be expressed in foci of neuroendorine differentiation {1026}. 2871.83 Chromogranin positivity in adenocarcinoma with eosinophilic granules. while others have not shown a prognostic relationship {30. synaptophysin. Definition Neuroendocrine differentiation in prostatic carcinoma has three forms: 1. di Sant’Agnese L.2472.1064.272. The Fig.Montironi M. Rubin W. 2582.A. The prognosis is uncertain due to the small number of reported cases.2583}. Tan A B Fig. 335. although the majority shows only rare or sparse single neuroendocrine cells as demonstrated by neuroendocrine markers.1222.2853. 609-611.1016. The prognostic significance of focal neuroendocrine differentiation in primary untreated prostatic carcinoma is controversial with some showing an independent negative effect on prognosis {267.2871} may be diagnostically and prognostically useful. Sakr P. Egevad J.2802.2465}.1185.2352. especially androgen independent cancer.A.2582} and may be a therapeutic target {228.1395. bombesin/gastrin-releasing peptide and a variety of other neuroendocrine peptides may also occur in individual neoplastic neuroendocrine cells. These tumours show classic cytologic features of carcinoid tumour and diffuse neuroendocrine differentiation (chromogranin A and synaptophysin immunoreativity). A subset of these neuroendocrine cells may also be serotonin positive. In advanced prostate cancer.1500.1183.2918}.

Using immunohistochemical techniques small cell components are negative for PSA and PAP.2254}. term "carcinoid-like tumours" has been used to refer to a variety of miscellaneous entities.1969}. serum PSA level falls and may be undetectable.84 Small cell carcinoma. Prognosis The average survival of patients with small cell carcinoma of the prostate is less than a year. only surgery was prognostic for prostate small cell carcinomas {1587}. There is no difference in prognosis between patients with pure small cell carcinoma and those with mixed glandular and small cell carcinoma. Neurosecretory granules have been demonstrated within several prostatic small cell carcinomas. In approximately 50% of the cases. While this study concluded that hormonal manipulation and systemic chemotherapy had little effect on the natural history of disease in the prostate. the number of patients were small and others suggest to treat small cell carcinoma of the prostate with the same combination chemotherapy used to treat small cell carcinomas in other sites {75. A Note extensive necrosis.2600}. Small cell carcinoma Clinical features Many patients have a previous history of a hormonally treated acinar adenocarcinoma. the tumours are mixed small cell carcinoma and adenocarcinoma of the prostate.A B Fig. The appearance of a small cell component within the course of adenocarcinoma of the prostate usually indicates an aggressive terminal phase of the disease. in order to distinguish them from a metastasis from the lung {37. While most small cell carcinomas of the prostate lack clinically evident hormone production. In a review of the literature of geni- 208 Tumours of the prostate . they account for the majority of prostatic tumours with clinically evident ACTH or antidiuretic hormone production. B Typical cytological appearance of small cell carcinoma. As the small cell carcinoma component predominates. most of which refer to ordinary acinar adenocarcinoma of the prostate with an organoid appearance and focal neuroendorcrine immunoreactivity. 3. tourinary small cell carcinoma. whereas cisplatin chemotherapy was beneficial for bladder tumours. Histopathology Small cell carcinomas of the prostate histologically are identical to small-cell carcinomas of the lung {2210. There are conflicting studies as to whether small cell carcinoma of the prostate is positive for thyroid transcription factor-1 (TTF-1).

1774}. although some cases have gone on to metastasize to distant sites. The appropriate treatment of STUMPs is unknown.Mesenchymal tumours J. Cheville F. and stromal overgrowth {844}. STUMPs are considered neoplastic. Epidemiology Sarcomas of the prostate account for 0. A Typical clover leaf architecture. There are several different patterns of STUMP. Although most cases of STUMP do not behave in an aggressive fashion. Boccon-Gibod A. Other stromal sarcomas consist of sheets of hypercellular atypical stroma without the fascicular growth pattern of leiomyosarcomas. When these lesions are extensive or associated with a palpable mass definitive therapy may be considered.85 STUMP (prostatic stromal proliferations of uncertain malignant potential) with benign glands and atypical stromal cells. Rare cases of adenocarcinoma of the prostate involving a phyllodes tumour have been identified. based on the observations that they may diffusely infiltrate the prostate gland and extend into adjacent tissues. Lesions have been classified into prostatic stromal proliferations of uncertain malignant potential (STUMP) and prostatic stromal sarcoma based on the degree of stromal cellularity.86 Benign phyllodes tumour. presence of mitotic figures. and could be termed in these situations as glandular-stromal or stromal nodule with atypia. and extensive overgrowth of hypercellular stroma with the histology of a stromal nodule.2% of all malignant prostatic tumours. Mesenchymal tumours 209 . ICD-O codes Stromal tumour of uncertain malignant potential Stromal sarcoma Leiomyosarcoma Rhabdomyosarcoma Malignant fibrous histiocytoma Osteosarcoma Chondrosarcoma Malignant peripheral nerve sheath tumour Synovial sarcoma Undifferentiated sarcoma Leiomyoma Granular cell tumour Fibroma Solitary fibrous tumour Haemangioma Chondroma are rare. Stromal sarcomas may have the overall 8935/1 8935/3 8890/3 8900/3 8830/3 9180/3 9220/3 9540/3 9040/3 8805/3 8890/0 9580/0 8810/0 8815/0 9120/0 9220/0 Fig. which neither recurs nor progresses. occasional cases have been documented to recur rapidly after resection and a minority have progressed to stromal sarcoma. and pleomorphism. including: those that resemble benign phyllodes tumour. 3. Tumours of specialized prostatic stroma Sarcomas and related proliferative lesions of specialized prostatic stroma glandular growth pattern of phyllodes tumours with obviously malignant stroma with increased cellularity. a subset of which is focal as seen on simple prostatectomy. Furusato A. STUMPs encompass a broad spectrum of lesions. Cheng J. such as rhabdomyosarcoma and leiomyosarco- A B Fig. 3. hypercellular stroma with scattered atypical yet degenerative cells. necrosis.10. Billis L. Algaba L.I. B Higher magnification discloses low cellularity and lack of atypia in epithelial and stromal elements. Lopez-Beltran Definition A variety of rare benign and malignant mesenchymal tumours that arise in the prostate {1063. and often recur. The behaviour of stromal sarcomas is not well understood due to their rarity. mitotic figures. Epstein M. Immunohistochemical results show that STUMP and stromal sarcomas both are typically positive for CD34 and may be used to distinguish them from other prostatic mesenchymal neoplasms.

. a few have recurred. the specialized prostatic stroma. There have been several well circumscribed lesions with a variable amount of nuclear atypia and scattered mitotic activity which have been referred to as atypical leiomyoma of the prostate {2233}.87 A Malignant phyllodes tumour. Leiomyosarcoma Leiomyosarcomas are the most common sarcomas involving the prostate in adults {443}. giant leiomyoma of the prostate {2162}. Although most "atypical leiomyomas" have shown no evidence of disease with short follow-up. Metastases. Both STUMP and stromal sarcomas characteristically express progesterone receptors (PR) and uncommonly express estrogen receptors (ER). whereas prostatic stromal sarcomas react negatively. B Leiomyosarcoma. 3. supporting the concept that STUMP and stromal sarcomas are lesions involving hormonally responsive prostatic mesenchymal cells. Histologically.A B Fig. A smaller. Most present with stage III disease. ma. but significant proportion of patients present with distant metastases. suggesting that the expression of muscle markers in these lesions is a function of differentiation.88 A Rhabdomyosarcoma. As with leiomyosarcomas found elsewhere. in which there is gross residual disease following incomplete resection or biopsy. B Angiosarcoma with slit-like spaces lined by atypical cells. though in some series up to 20% of leiomyosarcomas have occurred in young adults. Rhabdomyosarcoma Rhabdomyosarcoma is the most frequent mesenchymal tumour within the prostate in childhood {1522}. The average survival with leiomyosarcoma of the prostate is between 3 and 4 years. when present. these tumours immunohistochemically can express cytokeratins in addition to muscle markers. or circumscribed leiomyosarcoma of the prostate {2505}. High cellularity and cellular pleomorphism are obvious even at this magnification. The majority of patients are between 40 and 70 years of age. Fascicular arrangement. leiomyosarcomas range from smooth muscle tumours showing moderate atypia to highly pleomorphic sarcomas. STUMPS typically react positively with actin. Because smooth muscle tumours of the prostate are rare. Note strap cells. Following either local excision or resection of prostatic leiomyosarcomas. are usually found in the lung. 3. Rhabdomyosarcomas of the prostate occur from infancy to early adulthood with an average age at diagnosis of 5 years. the criteria for distinguishing between leiomyosarcoma and leiomyoma with borderline features have not been elucidated. Localized tumour that may be complete- A 210 Tumours of the prostate B Fig. Leiomyosarcomas range in size between 2 cm and 24 cm with a median size of 5 cm. the clinical course tends to be characterized by multiple recurrences. high cellularity and mitotic activity are characteristic.

Mesenchymal tumours 211 . distinction between rhabdomyosarcoma originating in the bladder and that originating in the prostate may be difficult. Following the development of effective chemotherapy for rhabdomyosarcomas. and neural tumours {1872} have also been described. Because of their large size at the time of diagnosis. and molecular techniques may be useful in the diagnosis of embryonal rhabdomyosarcoma. then radical surgery is performed. malignant peripheral nerve sheath tumours {2143}. those few patients with localized disease (stage I) or microscopic regional disease (stage II) stand an excellent chance of being cured. less than one hundred cases are reported.2079}. are described {1277}.89 Sarcoma of the prostate.1403. 3. Miscellaneous benign mesenchymal tumours Various benign soft tissue tumours have been described as arising in the prostate including granular cell tumour {824}. most prostate rhabdomyosarcomas are of the embryonal subtype and are considered to be of favourable histology. osteosarcoma {59. According to this definition. and solitary fibrous tumour {928. such as the bizarre leiomyoma. the usual therapy for localized disease is intensive chemotherapy and radiotherapy. Histologically.90 Solitary fibrous tumour. is a well-circumscribed proliferation of smooth muscle measuring 1 cm or more {1724}. approximately 15-20% die of their tumour. Other benign mesenchymal tumours such as haemangiomas {1112}. chondromas {2439}. angiosarcoma {2446}. Fig. to distinguish it from a fibromuscular hyperplastic nodule. Following biopsy or partial excision of the tumour. Fig. If tumour persists despite several courses of this therapy. with most patients dying of their tumour. Miscellaneous sarcomas Rare cases of malignant fibrous histiocytoma {158. 1899}. While the majority of patients with gross residual disease (stage III) have remained without evidence of disease for a long period of time. 3.1912. It is important to identify those rare cases of alveolar rhabdomyosarcoma involving the prostate since this histologic subtype is unfavourable and necessitates more aggressive chemotherapy. ultrastructural. ly resected is only rarely present. The use of immunohistochemical. 3. chondrosarcoma {631}.450.Leiomyoma The arbitrary definition of a leiomyoma. Fig.2369}.91 Solitary fibrous tumour. and synovial sarcoma {1189} have been reported. The prognosis for patients with metastatic tumour (stage IV) is more dismal. Its morphology is similar to uterine leiomyoma. and even subtypes.1741.

1% and 2. M.3% of men in whom tumours caused death {1699. 3.9% of all male postmortems {185. Iczkowski A. testis and endocrine glands have been reported {185. 30 and 10 cases were classified as primary.1699} and 1% and 6.2% of all surgical prostatic specimens {185}. 20% are reported to have prostate involvement at autopsy {2731}.93 Metastatic renal cell carcinoma to the prostate. Of patients with chronic lymphocytic leukaemia. Parkinson Epidemiology True metastases from solid tumours were reported in 0. Fig. Small lympocyte . Clinical context. morphological features and immunocytochemical localization of PSA and PSAP clarify the differential diagnosis.2905.A. 212 Tumours of the prostate . skin (melanoma). Secondary tumours involving the prostate Definition Metastatic tumours arise outside of the prostate and spread to the gland by vascular channels. Sixty cases were nonHodgkin lymphoma (predominately diffuse large cell followed by small lymphocytic lymphoma). In all series direct spread of bladder carcinoma is the commonest secondary prostatic tumour {185.like cells infiltrate the prostatic stroma. Lung was the most common primary site of metastases to the prostate {185}. Contiguous spread from other pelvic tumours into the prostate does not constitute a metastasis.The most frequent symptoms are those related to lower urinary obstruction. A B Fig. B Diffuse large cell lymphoma labeled with CD20. secondary and indeterminate respectively.A. In a recent large series of 62 cases.Haematolymphoid tumours K.C.1216}. 22.92 A Lymphocytic lymphoma. 3. Sakr The prostate is a rare site of extranodal lymphoma with a total of 165 cases arising in or secondarily involving the prostate reported. Haematolymphoid tumours of the prostate are discussed separately.2930} and in 0. gastrointestinal tract. Prognosis reflects the late stage of disease in which prostatic metastases are seen. kidney.2905}. Histopathology and prognosis Metastases from lung. Lopez-Beltran W.2930}. Rarely Hodgkin lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma were reported {291.

The patient may have elevated serum level of CA-125. Prostatic cystadenomas are not biologically aggressive {1611}. When cystadenomas occur within the prostate. Postulated causes include obstruction. Affected men are aged 20-80 years. reacting with antibodies to PSA and PSAP.500 grams.1501.1725. from the peripheral parenchyma {2004}. distinction from cystic nodular hyperplasia may be difficult. 2747}. Malignant rhabdoid tumour Malignant rhabdoid tumour may be found in the prostate {673}. They are well-circumscribed. resembling nodular hyperplasia with multiple cysts macroscopically. Furusato C. with high grade prostatic intraepithelial neoplasia reported in one case {62}. Pan ICD-O codes Cystadenoma Wilms tumour (nephroblastoma) Malignant rhabdoid tumour Clear cell adenocarcinoma Melanoma of the prostate Paraganglioma Neuroblastoma 8440/0 8960/3 8963/3 8310/3 8720/3 8680/1 9500/3 Cystadenoma Also known as multilocular cyst or giant multilocular prostatic cystadenoma. Haematolymphoid tumours /Secondary tumours involving the prostate / Miscellaneous tumours 213 .2872}. either separate from the prostate or attached to it by a pedicle. Although extra-adrenal paragan- A B Fig. ranging from 7. while the remaining gland is enlarged by a solitary encapsulated cystic nodule {1323. 3. or retrovesical ectopic prostatic tissue with cystic change {2872}. Intraprostatic cystadenoma should be diagnosed only when half the prostate appears normal. or exceptionally.5 cm to 20 cm in size. It is critical to exclude a metastasis from a testicular primary. It can develop from the prostatic urethra {636}. consistent with prostatic cystadenoma.Miscellaneous tumours P.94 Cystadenoma. Similar lesions can be found within the prostate gland. Germ cell tumours Primary germ cell tumours of the prostate have been rarely described {1046. A CT scan showing a large multinucleated cystic mass within the pelvis.1611. but can recur if incompletely excised. Cheng M. with or without a palpable abdominal mass {1324}.C. Cystadenomas weigh up to 6. Tan L. Primary malignant melanomas of the prostate are extremely rare {2493}. involutional atrophy {1594}. Müllerian derivatives such as Müllerian duct cyst {874}. Histologically. Malignant melanoma of the prostate should be distinguished from melanosis and cellular blue nevus of the prostate {2208}. B Gross section discloses large multicystic tumour. Clear cell adenocarcinoma Clear cell adenocarcinoma resembling those seen in the Müllerian system may affect the prostate. Paraganglioma Several case reports of paragangliomas originating in the prostate have been reported. 2586}. Extensive surgery may be necessary because of their large size and impingement on surrounding structures.H. The tumour cells immunohistochemically do not express prostate specific antigen and prostate acid phosphatase. it is composed of tubulocystic or papillary structures lined by cuboidal or hobnail cells with clear to eosinophilic cytoplasm. Atrophic prostatic epithelium lines the cysts. Wilms tumour (nephroblastoma) Melanoma of the prostate Wilms tumour rarely occurs in the prostate {386}.1704}. but may express CA-125. including one in a child {599. it is a rare entity characterized by benign multilocular prostatic cysts that can enlarge massively. It occurs between the bladder and the rectum {62. presenting with obstructive urinary symptoms.

have a less conspicuous. Acceptable reported cases numbered 48 {1977}. who usually have urinary obstruction as the main presenting symptom.1600. identical to what is seen with paragangliomas occurring in the bladder. Immunoreactive carcinoembryonic antigen (CEA) is detectable in normal seminal vesicle and seminal vesicle adenocarcinoma. and positive for CA125 (unlike carcinoma arising in a Müllerian duct cyst and all the above). less cellular stromal component than cystadenoma. The prognosis of primary seminal vesicle adenocarcinoma is poor. Clinical symptoms are similar to those of the adrenal (hypertension. mitotic activity or necrosis is seen {177. One man was cured by cystoprostatectomy {1451}.1659.1940}. The laboratory tests used to diagnose prostatic paragangliomas are the same as used to diagnose paragangliomas occurring elsewhere in the body. the stroma was at least focally densely cellular and tended to condense around distorted glands lined by cuboidal to focally stratified epithelium. Ultrasound reveals a complex. Samaratunga L.1451.1656}.M. Besides CEA. Although most were in older men. trabecular and glandular patterns with varying degrees of differentiation. Presenting symptoms usually included obstructive uropathy due to a nontender peri-rectal mass {212. ranging from 3 to 15 cm. Microscopically.1940} and less commonly haematuria or haematospermia. Tumours were grossly solid and cystic. The tumours occur in men in the sixth decade of life.2292}. The glands are grouped in a vaguely lobular pattern. Parkinson X. bladder. solid-cystic pelvic mass {1427}. Grossly. Helpap M. Carcinomas with colloid features have been described.1600. or rectal carcinoma {1977}. or rectum {212.C. No significant cytologic atypia. 3. ureter.gliomas should not be designated as "phaeochromocytomas". etc. Fig. headaches. 1451. Malignant behaviour has not been reported. five of 48 patients survived more than 18 months {1977}. Most patients presented with metastases and survival was less than 3 years in 95% of cases. Benign types include fibroadenoma and adenomyoma. Strict criteria for this diagnosis of this lesion require the exclusion of a concomitant prostatic. Benign and malignant mixed epithelial stromal tumours Epithelial-stromal tumours fulfill the following criteria: they arise from the seminal vesicle and there is no normal seminal vesicle within the tumour. Tumour cytoplasm may show clear cell or hobnail morphology. It is important to exclude a prostatic primary using PSA and PAP. Incompletely removed tumours may recur.95 Clear cell adenocarcinoma. Patients range in age from 37-66 years and may be asymptomatic or have symptoms of bladder outlet obstruction {177. Yang I. negative for cytokeratin 20 (unlike bladder and colonic carcinoma). this is a well-circumscribed tumour containing variablesized glandular spaces with branching contours and cysts with an investing spindle cell stroma.J. {1420}. Iczkowski H. they usually do not invade the prostate (one exception {1451}). rarely affects the prostate. they have been published as such. and are not immunoreactive for prostatic markers or CEA {737.). a primitive tumour of neuroectodermal origin. Four cases of malignant or probably malignant epithelial-stromal tumours have been reported {737. but can be improved with adjuvant hormonal manipulation {212}. These tumours have occurred in men aged 3966 who presented with pain and voiding difficulty.1656}. low-grade (below) is based on stromal blandness and inconspicuous mitotic activity. tumour should be positive for cytokeratin 7 (unlike many prostatic adenocarcinomas). The distinction from malignant epithelial-stromal tumour NOS.2292}.A. 10 men were under age 40 {212. Cheng B. symptoms have been exacerbated by urination (micturition attacks). 1322}. Histologically. contain pale intraluminal secretions and are lined by one or two layers of cuboidal to columnar cells. two had pelvic recurrence after 2 years. Serum carcinoembryonic antigen may be elevated up to 10 ng/ml. Pelvic organs may also be involved secondarily. The tumours are usually large (3-5 cm) and often invaded the bladder. Neuroblastoma Neuroblastoma. Tumours can show a mixture of papillary. Sesterhenn Epithelial tumours of the seminal vesicle Primary adenocarcinoma ICD-O code 8140/3 The seminal vesicle is involved by secondary tumours much more frequently than it contains primary adenocarcinoma. one cured by a second exci- Cystadenoma of the seminal vesicles ICD-O code 8440/0 Cystadenomas are rare benign tumours of the seminal vesicle. Tumours of the seminal vesicles K. These were categorized as low-grade or high-grade depending on mitotic activity and necrosis. the tumours were either multicystic or solid and cystic. 214 Tumours of the prostate . In some cases.

It may be difficult to ascertain the site of origin when adjacent pelvic organs are involved. When possible.850}. There is one case described as a "collision" tumour composed of liposarcoma of the seminal vesicles and prostatic carcinoma {1252}. B Higher magnification shows cellular details of the tumour. The patient presented with hypoglycemia. and was treated by cystoprostatectomy and vesiculectomy.A sion {1656} and one surgically incurable {1600}. although another developed renal metastasis after 2 years {1823}. angiosarcoma. Leiomyoma ICD-O code 8890/0 Angiosarcoma of the seminal vesicles is a highly aggressive tumour. Complete local excision appears to be curative. resection of the tumour mass by radical prostatectomy and vesiculectomy is the therapy of choice. leiomyoma. refractory to traditional surgical and adjuvant therapeutic modalities. Solitary fibrous tumour ICD-O code 8815/0 Angiosarcoma ICD-O code 9120/3 Three cases were reported {1785. excluding the testes. probably of Müllerian duct origin. in order from highest to lowest. and all were located in the right seminal vesicle. Fig. Some may be asymptomatic. with the largest deposit present in the seminal vesicle. ICD-O code 8850/3 A case of malignant haemangiopericytoma of the seminal vesicle has been reported {122}. is leiomyosarcoma. {738}. The frequency of these tumours. The patient died of distant metastasis from prostatic carcinoma. The therapy should be the complete surgical resection. magnetic resonance imaging. origin. Haemangiopericytoma ICD-O code 9150/1 Liposarcoma Leiomyoma of the seminal vesicles is asymptomatic and exceedingly rare. two died of distant metastasis within two months after the diagnosis {451.2006} and all presented with pelvic pain. in most cases by radical prostatectomy and vesiculectomy. Sonographic studies are important to establish the site of 8830/3 One case has been reported of primary choriocarcinoma of the seminal vesicles.1823. by magnetic resonance imaging {155.1432.2808}. 3. measures up to 5 cm {850}.1432}. Tumours of the seminal vesicles 215 By digital rectal examination and pelvic computed tomography as well as magnet- .96 A Adenocarcinoma of the seminal vesicles. The origin of the tumour was established by transrectal ultrasonography. this case is not definitive as there was tumour in multiple organs. Needle or open biopsy is required to establish the diagnosis. and detected by digital rectal examination and sonography. or computed tomography. The tumour. Six patients with reported seminal vesicle leiomyosarcoma presented with pelvic pain and obstructive symptoms but not haematuria (unlike with prostatic sarcoma) {87. The clinical presentations were pelvic pain or haematuria. solitary fibrous tumour. He died of disseminated haemangiopericytoma 10 years later. liposarcoma and haemangiopericytoma. 2332}. malignant fibrous histiocytoma. Among seven reported cases. Three cases were reported {451. Miscellaneous tumours of the seminal vesicle Choriocarcinoma ICD-O code 9100/3 Malignant fibrous histiocytoma Leiomyosarcoma ICD-O code ICD-O code 8890/3 This tumour is exceedingly rare in the seminal vesicle {538}. One patient was cured by radical cystoprostatectomy at 13-month follow-up {87}. a large pelvic mass in the region of the seminal vesicles of the prostate may be detected. Mesenchymal tumours of the seminal vesicles Mesenchymal tumours that arise in the seminal vesicles as a primary site are rare. However. and one developed lung metastasis 4 years postoperatively {737}. Local excision has yielded no recurrences. B ic resonance imaging. six were detected on digital rectal examination and one. Clinical presentations include pelvic pain and urinary or rectal obstructive symptoms.

characterized by high caloric diet and lack of physical xxxxxxxx. In most countries with an excellent clinical oncology infrastructure. Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx they have become the most common cancer in men aged 15 xxxxxxxx. exercise. In several regions. They mainly affect young males and xxxxxxxx. 44. .CHAPTER 4 X Tumours of thethe Xxx Tumours of Testis and Paratesticular Tissue Germ cell tumours are the most frequent and important Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx neoplasms at this site. Despite the increase in incidence rates. including North America and Northern Europe. There is circumstantial epidimiological evidence that the steep increase in new cases is associated with the Western Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx lifestyle. 5-year survival rates approach 95%. their incidence is steadily increasing in affluent societies. mortality from testicular cancer has sharply declined due to a very effective chemotherapy that includes cis-platinum.

unclassified Miscellaneous tumours of the testis Carcinoid tumour Tumours of ovarian epithelial types Serous tumour of borderline malignancy Serous carcinoma Well differentiated endometrioid carcinoma Mucinous cystadenoma Mucinous cystadenocarcinoma Brenner tumour Nephroblastoma Paraganglioma Haematopoietic tumours 9081/3 9085/3 9101/3 Tumours of collecting ducts and rete Adenoma Carcinoma Tumours of paratesticular structures Adenomatoid tumour Malignant mesothelioma Benign mesothelioma Well differentiated papillary mesothelioma Cystic mesothelioma Adenocarcinoma of the epididymis Papillary cystadenoma of the epididymis Melanotic neuroectodermal tumour Desmoplastic small round cell tumour 8591/1 8592/1 8590/3 9061/3 9063/3 9070/3 9071/3 9100/3 9073/1 8240/3 8442/1 8441/3 8380/3 8470/0 8470/3 9000/0 8960/3 8680/1 9104/1 9080/3 9084/0 9084/3 8140/0 8140/3 8650/1 8650/3 8640/1 8641/0 8642/1 8640/3 8620/1 8620/1 8622/1 8600/0 8810/0 9054/0 9050/3 9052/0 9055/0 8140/3 8450/0 9363/0 8806/3 Mesenchymal tumours of the spermatic cord and testicular adnexae Secondary tumours of the testis __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {808} and the Systematized Nomenclature of Medicine (http://snomed. mixed forms Malignant sex cord/gonadal stromal tumours Tumours containing both germ cell and sex cord/gonadal stromal elements Gonadoblastoma Germ cell-sex cord/gonadal stromal tumour. /2 for in situ carcinomas and grade III intraepithelial neoplasia. /3 for malignant tumours. Behaviour is coded /0 for benign tumours.WHO histological classification of testis tumours Germ cell tumours Intratubular germ cell neoplasia. unclassified Other types Tumours of one histological type (pure forms) Seminoma Seminoma with syncytiotrophoblastic cells Spermatocytic seminoma Spermatocytic seminoma with sarcoma Embryonal carcinoma Yolk sac tumour Trophoblastic tumours Choriocarcinoma Trophoblastic neoplasms other than choriocarcinoma Monophasic choriocarcinoma Placental site trophoblastic tumour Teratoma Dermoid cyst Monodermal teratoma Teratoma with somatic type malignancies Tumours of more than one histological type (mixed forms) Mixed embryonal carcinoma and teratoma Mixed teratoma and seminoma Choriocarcinoma and teratoma/embryonal carcinoma Others Sex cord/gonadal stromal tumours Pure forms Leydig cell tumour Malignant Leydig cell tumour Sertoli cell tumour Sertoli cell tumour lipid rich variant Sclerosing Sertoli cell tumour Large cell calcifying Sertoli cell tumour Malignant Sertoli cell tumour Granulosa cell tumour Adult type granulosa cell tumour Juvenile type granulosa cell tumour Tumours of the thecoma/fibroma group Thecoma Fibroma 9064/21 Sex cord/gonadal stromal tumour: Incompletely differentiated Sex cord/gonadal stromal tumours. 218 Tumours of the testis and paratesticular tissue . and /1 for borderline or uncertain behaviour.org).

or multiple lymph nodes.000 AFP (ng/ml) and <1. M1a M1. Stage III: Retroperitoneal lymph node involvement (>2cm) is present. see pT. none more than 2 cm in greatest dimension pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension.uicc. Stage II: Microscopic disease is located in the scrotum or high in the spermatic cord (<5 cm from the proximal end). Retroperitoneal lymph node involvement is present (<2cm).000–50.000 or >50. tumour may invade tunica albuginea but not tunica vaginalis pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion. where radical orchiectomy is not always necessary for classification purposes. or evidence of extranodal extension of tumour pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension S – Serum tumour markers SX Serum marker studies not available or not performed S0 Serum marker study levels within normal limits LDH <1. none more than 2 cm in greatest dimension N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension. M1a M1b S0. M1a M0 M1. Table 4. the extent of the primary tumour is classified after radical orchiectomy.000 or 5.000 or >10. histologic.5 x N 1. TX is used if no radical orchiectomy has been performed N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass 2 cm or less in greatest dimenion or multiple lymph nodes. No evidence of disease beyond the testis by clinical. M1a M0 M1.2 T – Primary tumour Except for pTis and pT4. none more than 5 cm.000 S1 S2 S3 N indicates the upper limit of normal for the LDH assay Stage grouping Stage 0 Stage I Stage IA Stage IB pTis pT1–4 pT1 pT2 pT3 pT4 Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX N0 N0 N0 N0 N0 N0 N0 N1–3 N1 N1 N2 N2 N3 N3 Any N Any N Any N N1–3 Any N N1–3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1. Serum AFP is persistently elevated. any one mass more than 2 cm but not more than 5 cm in greatest dimension N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non regional lymph node(s) or lung M1b Other sites pTNM pathological classification pT – Primary tumour pTX Primary tumour cannot be assessed (See T–primary tumour. histologic scar in testis) pTis Intratubular germ cell neoplasia (carcinoma in situ) pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion.000–10.000 or 1. or tumour extending through tunica albuginea with involvement of tunica vaginalis pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion pT4 Tumour invades scrotum with or without vascular/lymphatic invasion Stage IS Stage II Stage IIA Stage IIB Stage IIC Stage III Stage IIIA Stage IIIB Stage IIIC pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes. 2 A help desk for specific questions about the TNM classification is available at http://tnm. Stage I: Tumour is limited to testis. No visible evidence of visceral or extra abdominal involvement.282}.g.TNM classification of germ cell tumours of the testis TNM classification 1. above) pT0 No evidence of primary tumour (e. Stage IV: Distant metastases are present. In other circumstances. M1a M1.2662}. SX SX S0 S0 S0 S0 S1–3 SX S0 S1 S0 S1 S0 S1 SX S0 S1 S2 S2 S3 S3 Any S pN – Regional lymph nodes __________ 1 {944. or radiographic examination. 219 . or more than 5 nodes positive.5–10 x N >10 x N hCG (mIU/ml) and <5.org.01 Staging of germ cell tumours by the Paediatric Oncology Group (POG) {5. An appropriate decline in serum AFP has occurred (AFP t1/2 = 5 days).

The specimen should not be discarded until the clinician and the pathologist have agreed that the pathology report and diagnosis correlate with the clinical features. Tissue available for microscopic examination must include the tumour (at least one block for each 1 cm maximum tumour diameter and more if the tissue is heterogeneous). Spermatocytic seminoma and malignant lymphoma usually occur in older patients. If the metastases do not respond to the treatment. Sesterhenn The large majority of primary testicular tumours originate from germ cells. In addition to histological typing of the tumour. including the major dimensions. the estimated quantity of cell types. Further sectioning may identify an additional element in the primary tumour or a scar referred to as a regressed or burned out tumour. choriocarcinoma. Every cell type in the primary tumour. In the newborn. the non neoplastic testis. embryonal carcinoma. The presence of discor- dant findings (e.g. elevated AFP in a seminoma) indicates a need for further sectioning of the gross specimen.Introduction F. yolk sac tumour. The age of the patient provides a clue to the most likely type of tumour present. the histology of the untreated metastasis is identical to that of the primary tumour. Therefore. the epididymis. although both may also occur in younger individuals.A. determination of vascular/lymphatic invasion and the pathological stage of the tumour should be reported.and extratubular malignant germ cells. polyembryoma. the lower cord. it is essential that the specimen be examined adequately with extensive slicing and macroscopic description. the tunica nearest the neoplasm. 220 Tumours of the testis and paratesticular tissue . and teratoma. with or without intra. Before puberty. the most frequent testicular tumour is the juvenile granulosa cell tumour. In over 90%. In 10% of cases. Thus. while yolk sac tumour and the better differentiated types of teratoma are the usual germ cell tumours. Most germ cell tumours occur between the ages of 20 and 50 years. irrespective of its benign histological appearance or volume. is capable of invasion and metastasis. and the upper cord at the level of surgical resection. they may consist of some form of teratoma for which surgical intervention is the method of treatment. the histological features of the untreated metastases may be different from those of the initial sections of the primary tumour. seminoma is extremely uncommon. the information provided by the pathologist guides the urologic surgeon and the oncologist toward the best mode of therapy. Mostofi I. The TNM staging system is recommended. More than half of the tumours contain more than one tumour type: seminoma. The report of the pathologist can explain the relationship of the histology of the tumour to tumour markers and the response of the metastasis to the specific postorchiectomy treatment.K.

1766}. Thereafter. but the general shape of the curve is the same in low risk and in high risk populations {1766}. Michael V. Source: Thames Cancer Registry. Consistent with the geographical variation in incidence. Norway.Germ cell tumours P.W.K. This probably reflects the more rapid growth and the capacity of haematogenic spread and metastasis of non-seminomas. non-seminoma are similar. Sesterhenn H. The highest level of incidence. Oosterhuis D. The incidence increases shortly after the onset of puberty and reaches a maximum in men in the late twenties and thirties. The age incidence curves of seminoma and Fig. Rushton H. Age specific incidence rates of testicular cancer in South East England. Germany.02 Germ cell tumours. Grigor L. Looijenga J. 4. Ulbright I. Oliver A.C. The only population of non European origin with a similar high level of incidence is the Maori population of New Zealand with 7 per 100. Hungary and Switzerland {749}. McLeod H. is very different in populations with different levels of incidence. around 8-10 per 100.G.000 world standard population (WSP) are found in Denmark. Møller J.000 WSP. the risk of developing testicular tumour is susceptible to changes in everyday living conditions and habits.J.W.01 Germ cell tumours.H.D. the incidence of testicular germ cell tumours has been increasing in most populations of European origin in recent decades {481}.M. but appears to be highly and rapidly susceptible to increasing as well as decreasing levels of exposure to casual factors.000 of testicular cancer. Secondly. Finally. the Caribbean and Asia the level of incidence is typically less than 2 per 100.K. Hailemariam M. Talerman G. Jacobsen T. Manivel F. In Denmark. European annual incidence per 100. 19951999. Parkinson K. as these occurred with respect to changes in the supply and consumption situation in the Nordic countries during the Second World War. the age specific incidence rate decreases to a very low level in men in their sixties or older. Heidenreich L.A. Norway and Sweden the generally increasing incidence over time was interrupted by unusual low incidence in men who were born during the Second World War {222.J. Reuter Epidemiology The incidence of testicular germ cell tumours shows a remarkable geographical variation. the area under the age incidence curve Fig. From Globocan 2000 {749}. In general.E. The reasons for this phenomenon are not known but it illustrates several important characteristics. In populations in Africa. Kaplan T.C. that the risk of developing testicular cancer in men in high risk populations is not a constant. The age distribution of testicular germ cell tumour is unusual.G. True G. Mostofi S. but the modal age of non-seminoma is about ten years earlier than seminoma.000 WSP {2016}. 4. Firstly. Woodward A. the relatively low level of incidence throughout life of men in the Germ cell tumours 221 .

indicating a possible role of intrauterine growth retardation {43. The area under the age incidence curve may reflect the rate of occurrence of IGCNU. A similar association is evident for cryptorchidism and hypospadias {2797}. Etiology The research for the causes of testicular germ cell tumours has been guided by the hypothesis that the disease process starts in fetal life and consists of the abnormal differentiation of the fetal population of primordial germ cells. neonatal jaundice and retained placenta {2186. These tumours are not associated with ITCGNU and are not likely to be of prenatal origin. The incidence of testicular cancer is possibly increased in men with hypospadias and in men with inguinal hernia. Specific exposures For more than twenty years. both the undescended testicle and the normal. Intratubular germ cell neoplasia. Not infrequently. Clinical features Signs and symptoms The usual presentation is a nodule or painless swelling of one testicle. unclassified is practically always present in the tissue surrounding a testicular germ cell tumour and the condition has never been observed to disappear spontaneously. increase in the incidence of testicular cancer (about two fold) {2520}. The prevalence of carcinoma in situ in a population of men corresponds almost exactly to the lifetime risk of testicular cancer in these men. high maternal age.2775}. research in testicular cancer etiology has been influenced by the work of Brian Henderson and his colleagues who hypothesized an adverse role of endogenous maternal estrogens on the development of the male embryo {1070}. Prenatal risk factors Case control studies have shown consistent associations of testicular cancer with low birth weight and with being born small for gestational age. The presence of atrophy in maldescended testes is a major factor in germ cell neoplasia. however.900}. The association is very strong and very specific {1766}. This may be a tumour derived from the differentiated spermatogonia. contralateral testicle has an increased risk of testicular cancer {1768}. From these observations it may be inferred that the rate limiting step in testicular germ cell tumour is the abnormal differentiation of primordial germ cells leading to the persisting unclassified intratubular germ cell neoplasia which then almost inevitably progresses to invasive cancer. These are generally yolk sac tumour or teratoma. cancer {1768}. Atrophy adds to the risk of germ cell tumours in maldescent {613. Other. ranging from less than 1% in normal men in Denmark {891} to about 2-3% in men with a history of cryptorchidism {887} and 5% in the contralateral testicle in men who have already had one testicular germ cell tumour {614}.2186}. both in renal transplant patients and in AIDS patients seem to be associated with an increased incidence {245. A distinct peak in incidence of testicular tumours occurs in infants. Epidemiology and etiology of other testicular germ cell tumours Apart from testicular germ cell tumours in adult men. Their etiology is unknown. but their incidence level is much lower than in males {1767}. Immunosuppression.1769}. which have attempted to analyse the etiology of seminoma and non-seminoma separately. The empirical evidence. but not statistically significant. no consistent differences have emerged.wartime birth cohorts illustrate that the propensity to develop testicular cancer is established early in life. Testicular germ cell tumours are associated with intratubular germ cell neoplasia. for these hypotheses remains rather weak and circumstantial.1770}. however. More recently.2270. Exposures in adulthood There are no strong and consistent risk factors for testicular cancer in adulthood. which will be discussed in the genetic section. contralateral testicle have increased risk of testicular 222 Tumours of the testis and paratesticular tissue . There is no consistent evidence linking testicular cancer to particular occupations or occupational exposures. Ovarian germ cell tumours such as dysgerminoma (the female equivalent of seminoma) and teratomas may share important etiological factors with their male counterparts. Male infertility Subfertile and infertile men are at increased risk of developing testicular cancer {1203. In approximately 10% of patients evidence of metastasis may be the pre- Associations with congenital malformations of the male genitalia Cryptorchidism (undescended testis) is consistently associated with an increased risk of testicular germ cell tumour. Possible etiological clues. it may be of interest to note that there is a female counterpart to testicular germ cell tumours. unclassified (IGCNU). There are several strong indications that testicular germ cell tumour is associated with abnormal conditions in fetal life. It is most likely that the etiological factors in the two clinical subtypes of testicular germ cell tumour are the same {1769. a diagnosis of epididymitis is made. but the evidence is less strong than for cryptorchidism {2105}. several other types of gonadal tumours should be mentioned briefly. include a low level of physical activity and high socioeconomic class {4}. Follow-up of a cohort of men who were exposed in utero to the synthetic estrogen diethylstilboestrol have shown an excess occurrence of cryptorchidism and a possible. ultrasound may reduce the delay. The incidence is about 3-5 fold increased in men with a history of cryptorchidism {3}. Approximately one third of patients complain of a dull ache or heaviness in the scrotum or lower abdomen. Familial predisposition and genetic susceptibility are important factors in the development of testis tumours. In those with unilateral cryptorchidism. Finally. Spermatocytic seminoma occurs in old men. the emphasis has changed away from endogenous estrogens to environmental exposures to estrogenic and anti androgenic substances {2378}. These tumours do not seem to be associated with carcinoma in situ and their epidemiology and etiology are not well known. From the studies. The decline in the age specific incidence rates after about forty years of age may be due to the depletion of the pool of susceptible individuals with ITCGNU as these progress to invasive cancer {1766}.1020} and the normal. less consistent associations with testicular cancer include low birth order. It has been hypothesized that common causal factors may exist which operate prenatally and lead to both infertility and testicular neoplasia. In this situation.

When evaluating a palpable mass by ultrasound.378. however. medium level. over 50) Benign. colour Doppler is not of particular use in tumour characterization but does confirm the mass is solid {1126}. and there is a direct relationship between LDH and tumour burden. 2194. This is especially true in the region of the epididymal body and tail where normal structures can be difficult to visualize.5 days {305. 15-45) Seminoma Non-seminoma (embryonal carcinoma. It is elevated in 50-70% of testicular germ cell tumours and has a serum half life of 4. the so called TGCTs. If an extratesticular mass has any features suspicious of malignancy it must be removed.1965}: teratomas and yolk sac tumours of neonates and infants. Occasionally. lateral and anterior to the aorta. Y Gain: 12p*. The sonographic appearance of testicular tumours reflects their gross morphology and underlying histology. above the level of the inferior mesenteric artery. 20q. and medial to the vena cava. cough or dyspnoea. These retroperitoneal nodes drain from the thoracic duct into the left supraclavicular lymph nodes and the subclavian vein. alpha fetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (ßhCG). Somatic genetics Epidemiology. Other tumours can be heterogeneous with areas of increased echogenecity. With rare exception. The head of the epididymis is approximately 10-12 mm in diameter and is best seen in the longitudinal plane. clinical behaviour and genetic changes. and cyst formation {211. 7. AFP is normally synthesized by fetal yolk sac and also the liver and intestine. Germ cell tumours 223 Teratoma and/or yolk sac tumour Benign Malignant Not found Loss: 6q Gain: 1q . calcifications. solid intratesticular masses should be considered malignant. The former is seen in patients with yolk sac tumours and teratomas. appearing as a slightly rounded or triangular structure on the superior pole of the testis. It is easily performed and has been shown to be nearly 100% sensitive for identifying scrotal masses. 8.senting symptom: back or abdominal pain. histology. gastrointestinal problems. seminomas and non-seminomas of adolescents and young adults. be difficult to differentiate an epididymal mass from one originating in the spermatic cord or other paratesticular tissues. Although larger tumours tend to be more vascular than smaller tumours. but it is the beta subunit with a half life of 24-36 hours that is elevated in 50% of patients with germ cell tumours. characterized by age at clinical presentation. while the latter may be seen in any patients whose tumours include syncytiotrophoblastic cells. although can be associated with sarcoma Gain: 9 * found in all invasive TGCTs. Lactate dehydrogenase (LDH) may also be elevated. regardless of histology. 18. . alpha and beta. The epididymis is isoechoic to slightly hyperechoic compared to the testis. and all those with choriocarcinoma have elevated ßhCG {1333}. Also a normal level of each marker does not necessarily imply the absence of disease. There are two subunits. Intratesticular versus extratesticular pathology can be differentiated with 98-100% sensitivity {211. magnetic resonance (MR) imaging is seldom needed for diagnostic purposes. Since ultrasound is easily performed. It can. Gynecomastia may also be seen in about 5% of cases. histology of the tumour. anterior. however. this test is nonspecific although its degree of elevation correlates with bulk of disease. MR imaging can. and the spermatocytic seminomas of elderly. If postorchiectomy levels do not decline as predicted by their half lives to appropriate levels residual disease should be suspected.p.02 Overview of the three different subgroups of testicular germ cell tumours. Table 4. The left testis drains into lymph nodes distal. Tumour spread and staging The lymphatic vessels from the right testis drain into lymph nodes lateral. teratoma.2347}.378. Patients with seminoma may have an elevation of this tumour marker in 10-25% of cases. Most tumours are hypoechoic compared to the surrounding parenchyma. Computed tomography (CT) is not generally useful for differentiating scrotal pathology but is the primary imaging modality used for tumour staging. inexpensive. clinical behaviour. granular echo texture. the primary goal is localization of the mass (intratesticular versus extratesticular) and further characterization of the lesion (cystic or solid).p. The normal testis has a homogeneous. Epididymal masses are more commonly benign. 22 Aneuploid. However. 13. a thorough evaluation must be performed. Visualization of the epididymis is often easier when a hydrocele is present. Age of the patient at clinical presentation (years) 0-5 Histology of the tumour Clinical behaviour Chromosomal imbalances Tumour markers There are two principal serum tumour markers. extensive work ups have resulted without an adequate examination of the genitalia. yolk sac tumour.2362}. hCG is secreted by placental trophoblastic cells. and highly accurate. While most extratesticular masses are benign. X Adolescents and young adults (i.1541. and Loss: 11. be a useful problem solving tool and is particularly helpful in better characterizing extratesticular solid masses {507. choriocarcinoma) Spermatocytic Seminoma Malignant Malignant Elderly (i.927. and chromosomal constitution define three entities of germ cell tumours (GCTs) in the testis {1540. Imaging Ultrasound (US) is the primary imaging modality for evaluating scrotal pathology.1007.2194}.1333}.

XY gonadal dysgenesis are at very high risk of gonadal germ cell tumour.2334}. Although the role of genetic factors in the etiology of TGCTs appears to be established. Aneuploidy of TGCTs has been related to the presence of centrosome amplification {1653}. This could also explain the presence of telomerase activity in TGCTs. leading to a tetraploid IGCNU. Earlier age of onset. Seminoma and IGCNU cells are hypertriploid. Table 4.XY or 45. Although little is known about the pattern of genomic imprinting of spermatocytic seminomas {2726} the available data indicate that these tumours have already undergone paternal imprinting.2 11q12-13 Reference(s) Cell cycle control CDKN2C CDKN1A CDKN2B CDKN2A CDKN1B RB1 CDKN2D BCL10 FHIT TP53 MXI1 WT1 APC MCC NME1. No differences were detected between familial/bilateral and sporadic TGCT in chromosomal changes {2435}. Genomic imprinting Genomic imprinting refers to the unique phenomenon in mammals of the different functionality of a number of genes due to their parental origin. The absolute risk is reported to be as high as 10-50% {2267. a higher frequency of bilaterality and an increased severity of disease suggest that genetic anticipation is responsible for many father-son TGCTs {1014}. that also predisposes to undescended testis. 1962}. account for 1. Testicular germ cell tumours of adolescents and adults: Seminomas and non-seminomas Chromosomal constitution All TGCTs. except in (mature) teratomas {53}.2435}.2728}. This suggests that biallelic expression of imprinted genes in TGCTs is not the result of loss of imprinting (LOI) but is intrinsic to the cell of origin.9 for sons indicating that genetic predisposition is a contributor to testicular cancer {532}. environmental and heritable causes of cancer have been analysed by structural equation modelling {532}.3 for brothers and 3. 2148.2516} {299} {2436} {1116} {409} {1577} {2055} {2407} Cell survival/ Apoptosis Transcription Signaling Methylation Proteolysis Protein interaction Unknown 224 Tumours of the testis and paratesticular tissue . the existence of a single susceptibility gene is doubtful. However. Genetic susceptibility (familial tumours) Familial testicular germ cell tumours of adolescents and adults (TGCTs). for review].Similar tumours as those of group 1 and 2 can be found in the ovary and extragonadal sites.2129. The familial risks of TGCTs increase 3. (Putative) Pathway Gene Chromosomal mapping 1p32 6p21 9p21 9p21 12p12-13 13q14 19p13 1p22 3p14 17p13 10q24 11p13 5q21-22 5q21-22 17q23 18q21 18q21 10p15.X/46.1041.5-2% of all germ cell tumours of adults.1457. The estimate of proportion of cancer susceptibility due to genetic effects was 25% in adult TGCTs.2829} {1384} {1301} (for review) {2436} {1536} {2045} {2045} {161} {1856.1537.2703. This difference is generated during passage through the germ cell lineage.1053} {175} {2519} {176} {740. supporting the model that these tumours originate from an earlier stage of germ cell development than TGCTs.676.1914. a TGCT susceptibility gene on chromosome Xq27. while the tumour cells of non-seminoma. Relatively little is known on the genomic changes of these GCTs. This suggests that polyploidization is the initial event. Most probably genetic predisposition shared with intrauterine or childhood environmental effects are involved in the molecular pathogenesis of TGCTs. Supposedly the findings in the GCTs of the testis are also relevant for classification and understanding of the pathogenesis of ovarian and extragonadal GCTs.1742. Inter-sex individuals Persons with 46.1544.03 Tumour suppressor genes involved in the pathogenesis of testicular germ cell tumours (TGCTs). The childhood shared environmental effects were also important in testicular cancer (17%). The pattern of genomic imprinting has significant effects on the developmental potential of cells {2459}. including their precursor. Recently. in particular along the midline of the body.1 16p13 19q13 19q13 4p16.2697. Numerous groups have attempted to identify candidate regions for a TGCT susceptibility gene or genes {1386. The teratomas and yolk sac tumours of infants show a slightly different pattern of genomic imprinting {2243. intratubular germ cell neoplasia unclassified (IGCNU) are aneuploid [{567. 8. TGCTs show a consistent biallelic expression of multiple imprinted genes {882. followed by net loss of chromosomal material {1962}.2 DCC SMAD4 DNMT2 Testisin KALK13 NES1/KLK10 RNF4 hH-Rev107 {175} {175} {1053} {417. has been proposed by the International Testicular Cancer Linkage Consortium {2148}.8-fold for fathers. irrespective of their histological type are hypotriploid.2 726} as do mouse embryonic germ cells {2548}.

A B C Fig. Karyotyping.2 12q14-15 14q32.1794.and underrepresentation of (parts of) chromosomes in seminomas and nonseminomas.2436} {175} {175} {2135. 19. and subsequently found to be characteristic for TGCTs [{1743}. 4.04 Summary of the investigated proto-oncogenes studied for their involvement in the pathogenesis of TGCTs.2692}. and loss of the q-arm.2 1p34 2p24 20q13 3p21 12p12 17q11 17q11 12q24 11q12 Reference(s) Overrepresentation of 12p and candidate genes The only consistent structural chromoso- Cell cycle control CCNB CCND2 CCNA CCNE c-KIT FAS DAD-R MDM2 TCL1 E1F3S8 MYCL1 MYCN MYBL2 RHOA KRAS2 GRB7 JUP1 HIWI POV1 {175} {174. most often as i(12p) {2290}.2529}. while part of 12p is stained in green. 8. Their chromosomal localization is indicated. indicated by an arrow). Stem cell biology Unknown Germ cell tumours 225 .2250}. Interestingly. instead of non sister chromatin exchange {1827}.2518. anterior mediastinum and midline of the brain. but is also detected in these types of tumours in the ovary. 18 and Y are underrepresented. Normal centrosomes are indicated by an arrow. 880. The centromeric region of chromosome 12 is stained in red. 11.1953. while (parts of) chromosomes 7.03 Germ cell tumours genetics.1128. FISH. 5. for review]. A Example of G-banding of chromosomes 12 (left) and an isochromosome 12p (i(12p). in accordance to findings in TGCTs.04 Teratoma of the adult testis. up to 80%.2217.2199} {1869} {2251} {2436} {2436} {2436} {1262} {834. The i(12p) was initially reported in 1982 by Atkin and Baker {129. indicated by an arrowhead). as well as the references.2615} {2557} {2914} {1301.130}.1 16p11.1988. for review. This leads to the conclusion that gain of 12p-sequences is Table 4. This supports a common origin of all histological subtypes of these tumours. 12 and X are overrepresented. have i(12p) {2692}. 15. (Putative) pathway Gene Chromosomal localization 5q12 12p13 13q12. composed of both a seminoma and a non-seminoma component {388. Parts of chromosomes 4. B Schematic representation of a normal chromosome 12 (left) and an i(12p) (right).2692} revealed a complex but highly similar pattern of over. 4. CGH and spectral karyotyping (SKY) {388-390. Seminomas have significantly more copies of the chromosomes 7. explaining their higher DNA content {2235.2517. The candidates are classified based on the supposed biological pathway.2192. 1854. Note the presence of three normal chromosomes 12 (paired single red and green signals. 13.2535.1360. right) isolated from a primary non-seminoma of the adult testis. i(12p) is not restricted to the seminomas and non-seminomas of the testis. and the nuclei are counterstained in blue (DAPI). Fluorescent immunohistochemical detection of centrosome hypertrophy on a histological section.2436} {2436} {2436} {2123} {2436} Cell survival/ apoptosis Translation Transcription Signalling Fig. and hypertrophic centrosomes by an arrowhead.1829. mal aberration in invasive TGCTs is gain of 12p-sequences.3-13 19q1 4q12 10q24 12p11. The centrosomes are stained in red. and 22. C Representative example of fluorescent in situ hybridization on an interphase nucleus of a cell line derived from a primary non-seminoma of the adult testis.2325. and two i(12p)s (paired single red and double green signals. while the remaining cases also show additional copies of (part of) 12p {2216. Molecular analysis showed that the i(12p) is of uniparental origin {2428} indicating that its mechanism is doubling of the p-arm of one chromosome. The majority of TGCTs. 17.

Probably more genes on 12p. However.2436}. This suggests the existence of two pathways leading to overrepresentation of certain genes on 12p. A more focused approach to the identification of candidate genes was initiated by the finding of a metastatic seminoma with a high level of amplification of a restricted region of 12p. because of the aneuploid DNA content of TGCTs. and right is yolk sac tumour). In fact. Several candidate genes have been proposed to explain the gain of 12p in TGCTs. these data have to be interpreted with caution {1536}. Note the presence of a normal chromosome 12 (indicated by an arrow) and a chromosome 12 with a high level amplification (indicated by an arrowhead).06 Germ cell tumours genetics. even without the presence of a restricted amplification. and additionally a restricted high level amplification. 4. B G-banding (left) and fluorescent in situ hybridization with a 12pspecific probe stained in green on a metaphase spread of a primary testicular seminoma with a restricted 12p amplification (chromosomes are counterstained in red) (right). Subsequently. also known as POU5F1 {2003} X-inactivation {1538}. as well as their telomerase activity.2221.000 regions. Fig. 4.2 region in both the seminoma with and without the restricted amplification. help the tumour cells to overcome apoptosis {807}. in particular related to invasive growth {2236}. This could reflect simply their embryonic origin. in particular in the amplicon. Molecular genetic alterations Multiple studies on the possible role of inactivation of tumour suppressor genes and activation of proto-oncogenes in the development of TGCTs have been reported. as well as their embry- onic nature. which might not be involved in initiation of the malignant 226 Tumours of the testis and paratesticular tissue .1793. or an alternative mechanism. possibly followed by high level amplification.1 {2530}.2436}. and cyclin D2 (CCND2) {1128.07 Germ cell tumours genetics. 2192. Chromosomal expressed sequence hybridization (CESH) on A a seminoma with an isochromosome 12p. and gain of the short arm of chromosome 12. resulting in LOH. The latter might be involved via a deregulated G1-S checkpoint. and it is much rarer in non-seminomas. This is for example supported by their pattern of expression of OCT3/4. The seminomas with amplification have a reduced sensitivity to apoptosis for which DAD-R is a promising candidate {2914}. These data indicate that genes from this region are involved in the development of this cancer.2325. while it is present in the various types of invasive elements.2-p12. These included KRAS2. primary TGCTs have been found with such an amplification {1360.2404. A B Fig. expected to affect about 200. with the goal to identify candidate tumour suppressor gene-loci.2914}.1953.2147. in particular by means of detection of loss of heterozygosity (LOH). either via isochromosome formation.1795. A B Fig. cytogenetically identified as 12p11. Several studies have been done to identify genomic deletions. 4. The 12p-amplicon occurs in about 810% of primary seminomas. Interpretation of the findings must be done with caution if the data derived from the tumours are compared to normal testicular parenchyma. and the capacity of the non-seminomas to mimic embryonal and extra embryonal development. and B a seminoma with a restricted 12p amplification.2443}. which is rarely mutated and sometimes overexpressed in TGCTs {1818.1829. particularly in those lacking an i(12p) {2914}. which does not contain the normal counterpart of the cell of origin of this cancer.2-p12. A significant difference in genome methylation has been reported between seminomas (hypomethylated) and non-seminomas (hypermethylated) {882.05 Comparative genomic hybridization on isolated intratubular germ cell neoplasia unclassified (left) and three different histological variants of an invasive primary non-seminoma of the adult testis (left is embryonal carcinoma. A Representative comparative genomic hybridization results on chromosome 12 of a seminoma with an i(12p) (left panel). Note the absence of gain of 12p in the precursor lesion.crucial for the development of this cancer. aneuploid cells are thought to predominantly loose genomic sequences. Note the predominant expression of genes mapped within the 12p11. middle is teratoma.

data derived from these models must be interpreted with caution in the context of the pathogenesis of TGCTs.2. and that inactivation of TP53 explains only a minority of treatment resistant TGCTs {1129}.1 region. like their origin from IGCNU. 3p.process at all {1524}. 2p23-24. Recent findings indicating specific regions of amplification within the amplicon itself {1545. is a frequent finding in cisplatin refractory nonseminomas {1652}. {1541}. Chemoresistance of seminomas and non-seminomas has been related to high level genomic amplifications at 1q31-32. while a number of candidates were identified within the region of interest on 12p. This led to the view that high levels of wild type TP53 might explain the exquisite chemosensitivity of TGCTs. Fig. Two putative candidate genes (related to the ESTs Unigene cluster Hs. The other two studies focus on the short arm of chromosome 12. However. for review]. Expression profiles Three independent studies using array DNA and cDNA CGH on TGCTs have been reported. So far.08 Microsatellite instability (MSI) at locus D2S123 in a series of refractory germ cell tumours of the adult. In fact. 1q32. the seminomas of the rabbit {2717}.2771}. However. 3.1856. pluripotent embryonic stem cells show a different mutation frequency and type compared to somatic cells {397}. 9q32-34.1p15. the p11. 12q13 and q22. it was found that the GRB7 and JUP genes are overexpressed from the long arm of chromosome 17 and are therefore interesting candidates for further investigation. Therefore. 4. 1560. their postpubertal manifestation. leading to uniparental disomies.62275) referred to as GCT1 and 2 genes were identified to be overexpressed in TGCTs {300}.1384.2045}. respectively. immunohistochemical demonstration of MMR factors cannot predict MSI in these cancers. possibly due to a reduced nucleotide excision repair. embryonic cells show a higher tendency to chromosome loss and reduplication. the overall sensitivity of TGCTs might be related to their embryonic origin. embryonic characteristics.22595 and Hs.3-p32. In addition. Disturbed MMR. 5.p. 11.1853. Recurrent losses have been identified on 1p13. 7q31. No candidate gene has yet been identified at 12q22 {162} in spite of the identification of a homozygous deletion. 15q23-24. Germ cell tumours 227 . 9q22. and 20q11. The XPA gene.1652. However. 7q21.1561. TP53 and microsatellite instability and treatment response Immunohistochemistry demonstrates a high level of wild type TP53 protein in TGCTs. p22. and dog {1539}.672. apparent from microsatellite instability (MSI).1857. q14. However. the majority of LOH studies focused on parts of chromosomes 1. Low expression of XPA has been related to the sensitivity of TGCT to cisplatin based chemotherapy {1342}. However.1855. The underlined cases show MSI. Some of the candidate tumour suppressor genes mapped in the deleted genomic regions in TGCTs have been investigated. are most likely informative models for the infantile teratomas and yolk sac tumours and the spermatocytic seminomas. and the possible combination of seminoma and non-seminoma. The second study on 12p {2219}.1536. and q34-qter.1581. horse {2716}. the mouse teratocarcinomas and canine seminomas. 12 and 18 {162.2044}. In addition. i. and amongst others a gene related to ESTs AJ 511866. for review see ref. p31. q21. and more recently the GDNF induced seminomatous tumours in mice {1712}. Animal models A number of animal models have been suggested to be informative for the development of TGCTs. which are detected as LOH.1645.2915} will facilitate further investigation of the gene(s) involved. like the mouse teratocarcinoma {1580. The first {2436} showed that gene expression profiling is able to distinguish the various histological types of TGCTs using hierarchical cluster analysis based on 501 differentially expressed genes. reports that BCAT1 is an interesting candidate for non-seminomas specifically. Shown are the results in normal peripheral blood DNA (indicated by "N") and matched tumour DNA ("T").2-p12. In fact. it has been shown that this is an oversimplification [{1301}. That this region is indeed of interest is demonstrated by the finding that TGCTs without a restricted 12p amplification do show preferential overexpression of genes from this region {2219}. including EKI1. 5p15. but not in TGCTs in general {603. these candidates map outside the region of interest as found by earlier studies and are expressed ubiquitously. none of these include all the characteristics of human TGCTs. maps to 9q22. and initiation of apoptotic programs rather than repair. Another mechanism of resistance against cisplatin is interruption of the link between DNA damage and apoptosis. q11. involved in DNA repair. in contrast to the majority of solid cancers. inactivating mutations are hardly found.2-12 {2147}. as well as the HPV{1351}. A high expression of the DNA base excision repair has been suggested for chemoresistance in TGCTs {2212}. and 18q. so far. However. The mismatch repair pathway (MMR) is most likely involved in the detection of DNA damage.

1985. 228 Tumours of the testis and paratesticular tissue .387. while numerical changes are present. 4.2222} in contrast to 0.345. Patients with intersex syndrome.1831.2140. 2826}. Since the risk of tumour development in the contralateral testis is increased about 2550 fold {615. the prevalence is about 1% {233. intratubular preinvasive tumour. IGCNU is detected in 42% of patients who presented with retroperitoneal germ cell tumours {262.5% in young children {501}.2167.2483}. Note the almost complete absence of structural anomalies.1100} but is rarely found in patients with mediastinal tumours {997}.2040. Several autopsy studies have shown that the incidence of IGCNU is the same as the incidence of germ cell tumours in the general population {616.4% of cases. 2018.A B Fig. and a Y chromosome have intratubular germ cell neoplasia of the unclassified type (IGCNU) in 6-25% of cases {118. irregular nuclei and prominent nucleoli located within the seminiferous tubules. carcinoma in situ.2749}. A Intratubular germ cell neoplasia (IGCNU) adjacent to normal seminiferous tubules. 4. the true incidence of prepubertal IGCNU is difficult to assess. unclassified are seen in 2-4% {345. 2430.1381. ICD-O code 9064/2 Synonyms Intratubular malignant germ cell. some centres in Europe have initiated biopsies of the contralateral testis. A Example of G-banding on a metaphase spread.891}.10 Precursor lesions of germ cell tumours.2943}) ranging from 0-5%. Testes harbouring a germ cell tumour contain IGCNU in a mean of 82. with detection rates of IGCNU of 4. A B Fig.2346. Precursor lesions Intratubular germ cell neoplasia. found IGCNU in 2 of 87 cases of different intersex states {2140}. ranging from 63 {889} -99% {346}. In review of the literature Ramani et al. unclassified type (IGCNU) Definition Germ cells with abundant vacuolated cytoplasm. 1010. Four of 4 patients with gonadal dysgenesis in one series had intratubular germ cell neoplasia of the unclassified type (IGCNU) {1833} as did 3 of 12 patients with androgen insensitivity (testicular feminization) syndrome {1831}. intratubular atypical germ cells and intratubular malignant germ cells. testicular intraepithelial neoplasia. Gain of chromosome 9 is the only consistent anomaly identified.09 Spermatocytic seminoma. Epidemiology Adults In adults with history of cryptorchidism intratubular germ cell neoplasia. Children In contrast to their adult counterpart.2131. gonocytoma in situ.555. B Comparative genomic hybridization of DNA isolated from the same tumour.9-5.787.1900.7% {613.2482. B Positive PLAP staining in the intratubular germ cell neoplasia (IGCNU) adjacent to normal seminiferous tubules. IGCNU is seen in association with cryptorchidism is 2–8% of patients {1381}. In infertility studies. 2774}. large. IGCNU has only rarely been described in association with testicular maldescent.1124. intersex states and in a very few case reports of infantile yolk sac tumour and teratoma {1134.887.

suggests that the pathogenesis of germ cell tumours in children may be different than in adults.890}.2763}. Macroscopy There is no grossly visible lesion specific for IGCNU.2061} and TRA-1-60 {97. Mitoses.2518}. patients. The morphologic and the immunohistochemical features of normal prepubertal germ cells resemble those of IGCNU and can persist up to 8 months to one year of age {118}. 1302. A Typical pattern of intratubular germ cell tumour unclassified. Isolated malignant germ cells in the interstitium or lymphatics represent microinvasive disease. Clinical features The symptoms and signs are those of the associated findings. B PAS staining for glycogen in the malignant germ cells. 886}. with mean 25 years follow up. The malignant germ cells are also seen in the rete and even in the epididymal ducts. unclassified. C Positive PLAP staining in the malignant germ cells.345. 4.151.1345. 4.13 Precursor lesions of germ cell tumours. for example: TRA-1-60 is seen in tubules adjacent to Germ cell tumours 229 . Spermatogenesis is commonly absent. The tubular involvement is often segmental but may be diffuse.1615. C Fig.1199. 43-9F {889.A B Fig.346. B Syncytiothrophoblasts in a tubule with intratubular germ cell neoplasia (IGCNU). infertility. but occasionally one can see a pagetoid spread in tubules with spermatogenesis. Immunoprofile PLAP can be demonstrated in 83-99% of intratubular germ cell neoplasia of the unclassified type (IGCNU) cases and is widely used for diagnosis {189. One study found no testicular cancer in 12 of the 22 prepubertal Histopathology The malignant germ cells are larger than normal spermatogonia. irregular and hyperchromatic with one or more large.11 Precursor lesions of germ cell tumours. as demonstrated by periodic acid-Schiff (PAS) stains. Other markers include: CD117 (c-kit) {1191. Note the large nuclei with multiple nucleoli. A B Fig. the validity of prepubertal IGCNU needs further investigation.1054. 4. The cells are usually basally located between Sertoli cells. are not uncommon. including atrophic testis. irregular nucleoli.12 Comparison of morphological features of normal seminiferous tubules (left part) and intratubular germ cell neoplasia (IGCNU) in seminiferous tubules (right part). The nuclei are large. Therefore. overt tumour and intersex features. They have abundant clear or vacuolated cytoplasm that is rich in glycogen. 888. M2A {157. These markers are heterogeneously expressed in IGCNU. maldescended testis. A lymphocytic response often accompanies both intratubular and microinvasive foci.1100. The absence of isochromosome 12p in testicular germ cell tumours of childhood. including abnormal ones.1619. who were biopsied during orchidopexy and found to have placental alkaline phosphatase (PLAP) positive atypical appearing germ cells {996}. A Intratubular germ cell neoplasia.

230 Tumours of the testis and paratesticular tissue .2750}. Note the lymphocytic infiltration.A B Fig. which lacks the nuclear features of IGCNU and PLAP reactivity. CGH has shown that IGCNU adjacent to invasive TGCTs have Tumours of one histological type Seminoma Definition A germ cell tumour of fairly uniform cells. If both tumour types are present.892. the chromosomal constitution of IGCNU. Giant spermatogonia have a round nucleus with evenly dispersed chromatin and are solitary and widely scattered. and gain of 2p {2694}. In non white populations trends in incidence are not uniform including both an increase (Singapore Chinese. with the absence of gain of 12p being the major difference {1543. Fig. Prognosis About 50% of cases progress to invasive germ cell tumours in 5 years and about 90% do so in 7 years.14 Intratubular germ cell neoplasia (IGCNU).676.1830. These statements are based on retrospective follow-up of infertile men with IGCNU or prospective surveillance of patients with a treated TGCT or IGCNU in the contralateral testis {233. 4. In fact.2116. Differential diagnosis IGCNU has to be distinguished from spermatogenic arrest at spermatogonia stage. non-seminomatous germ cell tumours but not seminoma {886}. It can therefore be concluded that gain of 12p is not the initiating event in the development of TGCTs. with one or more nucleoli.2216. less frequent loss of parts of chromosome 4 and 13. Hydrocele may be present.2409}.2132}. in line with earlier observations {861}. the rate doubling about every 30 years. B Higher magnification discloses cytological features of IGCNU.15 Intratubular germ cell neoplasia (IGCNU) and microinvasion.1895. Clinical features Signs and symptoms The most common mode of presentation is testicular enlargement. and well defined cell borders.2536}. Genetics The DNA content of IGCNU has been reported to be between hypotriploid and hypopentaploid {567. adjacent to an invasive TGCT is highly similar to the invasive tumours. 4. a large regular nucleus.1900}. This demonstrates that polyploidization precedes formation of i(12p). Intratubular seminoma distends and completely obliterates the lumina of the involved tubules. A Spread of malignant germ cells to rete.2236. These findings support the model that IGCNU in its karyotypic evolution is only one step behind invasive TGCTs {1964}. containing cytoplasm. New Zealand Maoris and Japanese) and no increase (US Blacks) {2017. which is usually painless. typically with clear or dense glycogen Epidemiology The increase in the incidence of testicular germ cell tumours in white populations affects seminoma and non-seminomatous neoplasms equally. the expression is even more heterogeneous. ICD-O code 9061/3 Ultrastructure By electron microscopy the IGCNU are very similar to prespermatogenic germ cells in their early stage of differentiation {911.2431}. Intratubular spermatocytic seminoma shows the 3 characteristic cell types. Rare cases may not progress {345.

Seminomas can be lobulated or multinodular. Cyst formation and haemorrhage are uncommon. A tubular pattern may occur. Larger tumours can completely replace the normal parenchyma and may be more heterogeneous. 4. A Seminoma cells with finely granular eosinophilic cytoplasm. A small hydrocoele may be present but it is unusual for seminoma to spread into the vaginal sac. A small rim of normal. Fig. these nodules are most commonly in continuity with one another. however. Histopathology Seminomas are typically composed of uniform cells arranged in sheets or divided into clusters or columns by fine fibrous trabeculae associated with a lymphocytic infiltrate. Less frequently appearances include dense fibrous bands and "cystic" spaces produced by oedema within the tumour. alpha-fetoprotein (AFP) and CD30. Mitoses are variable in number. hypoechoic mass (arrows). they have more densely staining cytoplasm. Tumour spread into the epididymis and cord is rare. B Intratubular typical seminoma.17 Seminoma. B Longitudinal ultrasound image of the tesits shows lobular. well defnined. cream or pale pink soft homogeneous lobulated mass with a clear cut edge and may have irregular foci of yellow necrosis. Seminomas usually obliterate testicular architecture but other growth patterns include: interstitial invasion (or microinvasion) in a A B Fig. more hyperechoic. Tumour spread Seminoma metastasizes initially via lymphatics to the paraaortic lymph nodes. 4. Imaging Seminoma has one of the more sonographically characteristic appearances of the testicular tumours. Seminoma cells are round or polygonal with a distinct membrane. Granulomatous reaction and fibrosis are common and occasionally so extensive that the neoplasm is obscured. B Nodular architecture. They are generally well defined and uniformly hypoechoic. Characteristically a seminoma forms a grey. Seminoma with high mitotic rate Seminomas with a greater degree of cellular pleomorphism. pseudoglandular and tubular variants of seminoma The seminoma cells may be arranged in a nested pseudoglandular/alveolar or “cribriform” pattern with sparse lymphocytes {549}. A Typical homogenous whitish seminoma. lung. A Transverse ultrasound image of the testis shows a large. Confirmation of pure seminoma may require demonstration of positive staining for placental alkaline phosphatase (PLAP) and CD117 (C-Kit) with negative staining for inhibin. Macroscopy The affected testis is usually enlarged although a proportion of seminomas occurs in an atrophic gonad. Nuclei contain prominent nucleoli. 4. parenchyma remains (black arrows). well defined. which may be bar shaped.16 Seminoma. Less commonly. uniformly hypoechoic mass (white arrow). which may be dense with follicle formation. Nodules separate from the main mass may be seen and occasionally the tumour is composed of numerous macroscopically distinct nodules. Cytoplasm is usually clear reflecting the glycogen or lipid content.18 Seminoma. resembling Sertoli cell tumour {2892}. bones and other organs. A B Variants Cribriform. and afterward to the mediastinal and supraclavicular nodes. A B Germ cell tumours 231 Fig. higher mitotic activity and a sparsity of stromal lymphocytes have been called atypical seminoma. Plasma cells and eosinophils may also occur on occasion. Haematogeneous spread occurs later and involves liver.small tumour insufficient to produce a palpable or macroscopic mass or at the edge of a large tumour. intratubular infiltration. Veins in the tunica are prominent. . pagetoid spread along the rete.

and may have intracytoplasmic lacunae. support embryonal carcinoma. Immunoprofile Placental alkaline phosphatase (PLAP) is Differential diagnosis Seminomas are occasionally misdiagnosed {1463. higher S-phase fraction. In differential diagnostic contexts the following are helpful: Seminoma versus embryonal carcinoma – a combination of negative CD117 and positive CD30 {1478. however. increased mean nuclear volume. The prognostic significance of these features. Note the association with haemorrhage. These are not always subdivided into a separate category of seminoma because their clinical outcome is similar to classical seminoma {2542. seen diffusely in 85-100% of classical seminomas with a membranous or perinuclear dot pattern {444. Higher levels may indicate bulky disease but possibly choriocarcinoma {1123. and do not have the features of choriocarcinoma.2946}. However. some studies indicate that seminomas with high mitotic counts. B High mitotic rate seminoma.2616}.2616}. 4.20 Seminoma.2353}. classical seminoma versus spermatocytic seminoma – widespread PLAP indicates the former.2664}.2806}. They may be surrounded by localized areas of haemorrhage although they are not associated with cytotrophoblastic cells. higher incidence of metastasis {817. CK8. hCG positive cells may be identified in up to 25% of seminomas {1202. 232 Tumours of the testis and paratesticular tissue . widespread membranous pancytokeratins. 4. 18 or 19 {2664}. The presence of hCG positive cells is frequently associated with elevated serum hCG (typically in the 100s mIU/ml) {1033}.A B Fig.1809. Seminomas with STCs or elevated serum hCG do not have a poorer prognosis in comparison to classic seminoma of similar volume and stage {1123.21 Seminoma with syncytiotrophoblasts. the distinc- A B Fig. 4. The STCs are usually multinucleate with abundant slightly basophilic cytoplasm.2664} and persists in necrotic areas {780}. or seminoma with high mitotic index {1805. Other giant cells are frequently seen in seminomas and may be non neoplastic Langhans giant cells associated with the inflammatory stromal response. Fig. Angiotensin 1-converting enzyme (CD 143) resembles PLAP and CD117 in distribution {2618} but is not in widespread diagnostic use. VASA is extensively positive {2929}. A Seminoma with dense cytoplasm and pleomorphic nuclei. remains controversial {444}. however. and are at a higher stage at clinical presentation {1873. In contrast.2616}.1122}. Seminoma with syncytiotrophoblastic cells Tumour giant cells are also seen with morphological and ultrastructural features of syncytiotrophoblastic cells (STC) {2355}. These cells stain for hCG and other pregnancy related proteins and cytokeratins {550}.2603}.2780}.1803} some of which are mononuclear cells. although some have sparse cytoplasm with crowded aggregates of nuclei having a “mulberry-like” appear- ance. B Granulomatous stromal response. A Typical seminoma with pronounced infiltration of lymphocytes. and aneuploidy have a poorer prognosis {1778.2806}. Rarely. C-Kit (CD117) has a similar established incidence and distribution {1478. Up to 7% of classical seminomas have recognizable STCs.2 and AE1/3) and CD30 are less frequently seen and usually have a focal distribution {444. anaplastic seminoma.19 Seminoma. pancytokeratins (Cam 5.

g. 82 and 64% for tumours <3. in which tubule formation may resemble the tubular variant of seminoma: metastases (e. and tunical invasion have all been related to clinical stage at presentation {1626. Conversely. the absence of IGCNU and the demonstration of either the typical seminoma immunophenotype or the immunocytochemical features of Leydig.23 Positive staining for PLAP in typical seminoma. Views are not uniform on the value of cytokeratins and CD30 for predicting prognosis {444. tion between seminoma and embryonal carcinoma is difficult with respect to an area within a tumour or the entire neoplasm. 4.22 Seminoma. necrosis. Extensive sampling and a high power search for seminoma cells (supported by PLAP and CD117 content) help reduce such errors. C Cribriform variant of seminoma. these include: spermatocytic seminoma. The florid lymphocytic or granulomatous response within seminoma occasionally prompts the misdiagnosis of an inflammatory lesion. possibly as a consequence of their rarity. Prognosis and predictive factors The size of the primary seminoma. (especially those with clear/vacuolated cytoplasm). especially on frozen section. The 4 year relapse free survivals were 94. Leydig cell tumours. vascular space. Morphological discrimination features include: the discrete uniform cells of seminoma which contrast with the pleomorphic overlapping cells of embryonal carcinoma. With respect to patients with stage I disease managed on high surveillance protocols. 4. other tumours are occasionally misinterpreted as classical seminoma. PLAP and CD117 are distributed more diffusely in seminoma than embryonal Fig.2781}. respectively {2751}. B Cords of tumour cells in seminoma.A B C D Fig. Sertoli cell tumours. In all these neoplasms. Blood and lymphatic channel invasion was seen more commonly in association with relapse but statistical significance is not consistent. carcinoma. Spermatocytic seminoma Definition A tumour composed of germ cells that Germ cell tumours 233 . Sertoli or the specific metastatic tumour should limit error. melanoma).2616}. 3-6 and 6 cm. the lymphocytic and granulomatous response typical of seminoma but rare in embryonal carcinoma.2616}. D Alveolar variant of seminoma. whereas CD30 and pancytokeratin are more pronounced in embryonal carcinoma. A Pseudoglandular variant of seminoma. retrospective studies have emphasized the size of the primary and invasion of the rete testis as independent predictors of relapse {1202.

These often have the typical spireme like chromatin distribution. haemorrhagic and even necrotic.2229. cystic. ICD-O code 9063/3 Epidemiology Spermatocytic seminoma is rare. unlike other germ cell tumours.1805. The malignant germ cells (IGCNU) in adjacent tubules typically associated with other germ cell tumours are not present. but others had negative results.1195. Mitoses. Sometimes. The predominant cell type is round of varying size with variable amounts of eosinophilic cytoplasm. The tumours are often soft. CD30 are not demonstrable. The second type is a small cell with dark staining nuclei and scant eosinophilic cytoplasm. Lymphocytic infiltration and granulomatous stromal reaction are only rarely seen. Note the mucoid appearence.5 percent {347. The tumour consists typically of 3 basic cell types {347. Immunoprofile Many of the markers useful in other types of germ cell tumour are generally negative in spermatocytic seminoma. The third cell type is a mono-. The adjacent seminiferous tubules often show intratubular growth. Macroscopy The size ranges from 2 to 20 cm with an average of 7 cm {347}. The oedema may cause a “pseudoglandular” pattern.25 Spermatocytic seminoma. its frequency varying from 1. Cytokeratin 18 has been demonstrated in a dot-like pattern {527. Fig.784}. Germ cell Fig. 234 Tumours of the testis and paratesticular tissue .347. Glycogen is not demonstrable. Most tumours are unilateral. NY-ESO-1. vary in size from lymphocyte-like to giant cells of about 100 μm in diameter. There is no difference in race predilection from other germ cell tumours. CD117 (c-kit) has been reported to be positive {2299}.1195. Histopathology The tumour cells are noncohesive and are supported by a scant or oedematous stroma. oval or indented nuclei. There may be vascular. CEA. 4. The round nucleus often has a lacy chromatin distribution with a filamentous or spireme pattern similar to that seen in spermatocytes. Vascular invasion. a cancer specific antigen. Generally symptoms although wider sampling reveals characteristic areas {55}.2 to 4. They have been described as lobulated. Spermatocytic seminoma occurs only in the testis. AFP.347. Extension into paratesticular tissue has been rarely reported {2349}. desmin. hCG.582}. Collagen bands may enclose tumour compartments. tunical and epididymal invasion. VASA is diffusely reactive {2929} PLAP has been observed in isolated or small groups of tumour cells {346.2565}.26 Spermatocytic seminoma devoid of stroma and very edematous. LCA. well circumscribed with bulging mucoid cut surfaces. which may be seen in the ovary and elsewhere. Bilateral tumours are more often metachronous {220. including abnormal forms are frequent. was found in 8 of 16 spermatocytic seminomas but not in other germ cell tumours {2299}.consist of painless swelling of variable duration {347}.2565}.24 Seminoma. Serum tumour markers are negative. In a series of 79 cases {347} none of the patients had a history of cryptorchidism. Clinical features Most tumours occur in the older male with an average age of 52 years but it can also be encountered in patients in their third decade of life. the cells are relatively monotonous with prominent nucleoli Fig.1644. 4. 4.2349}. 1800. rarely multinucleated giant cell with round. with the bulk of the tumour composed of cells of intermediate size. actin.

The differential diagnosis of a tumour where only the sarcoma component is sampled includes primary testicular sarcoma {408. including diploid or near hyperdiploid values {582. Absence of teratoma and recognition of the spermatocytic seminoma excludes this possibility. and focal myxoid change.2786. spindle cell sarcoma. and chondrosarcoma {347. These data are in keeping with the finding that spermatocytic semi- Spermatocytic seminoma with sarcoma Definition A spermatocytic seminoma associated with an undifferentiated or. association. CGH and karyotyping show mostly numerical chromosomal aberrations. 1649.783. Fig. Gap junctions and macula adherens type junctions can be observed. a feature that is diagnostically helpful {2512}. including SCP1 (synaptonemal complex protein 1). Levels of serum alpha-fetoprotein and human chorionic gonadotropin are normal. usually has a fibrous stroma. Fifty percent of patients have metastases at diagnosis. when misinterpreted. 2146}. This might explain the relatively frequent occurrence of bilateral spermatocytic seminoma (5% of the cases). There are intercellular bridges like those between primary spermatocytes {2226}. B noma cells show characteristics of cells undergoing meiosis.2234. A Note the three different cell types of spermatocytic seminoma.1800. however. although puf-8 recently identified in C. elegans might be an interesting candidate {2524}.2950}.rhabdomyosarcoma.2646}.A maturation stage specific markers. The chromatin is either homogeneously dispersed or has dense condensations and nucleoli have net-like nucleolonema {2299}. SSX (synovial sarcoma on X chromosome) and XPA (xeroderma pigmentosum type A1). The sarcoma can exhibit various patterns . No gene or genes involved in the pathogenesis of spermatocytic seminomas have been identified yet.1832. and IGCNU component.753. Seminoma.2568}. Most patients die of metastatic tumour. paratesticular sarcoma. have been demonstrated {2512}. Clinical features Approximately a dozen cases of this tumour have been reported. Macroscopy Typically the tumour is a large (up to 25 cm). The presence of common chromosomal imbalances in a bilateral spermatocytic seminoma and immunohistochemical characteristics {2512} suggests that the initiating event may occur during intra-uterine development.27 Spermatocytic seminoma. Lymphoma has a predominant interstitial growth pattern and lacks the spireme chromatin distribution. Haploid cells have not been reported {1385. 4. PLAP positivity. The age range is 34-68 years. Differential diagnosis Spermatocytic seminoma. with a median surGerm cell tumours 235 . with a differentiated sarcoma. a lymphocytic and/or granulomatous stromal reaction and cells with abundant glycogen. and no etiologic agents have been identified. and is histologically contiguous with the sarcoma component. less frequently.769. and metastatic sarcoma or sarcomatoid carcinoma {510. necrosis. Genetics The DNA content of spermatocytic seminoma is different from that of seminoma.2568}. Ultrastructure The cell membranes lack folds and indentations. The typical patient has a slowly growing mass that suddenly enlarges within months of diagnosis. Histopathology The spermatocytic seminoma component frequently has foci of marked pleomorphism {647}. B Intratubular spread of spermatocytic seminoma. bulging mass with variegated cut surface exhibiting areas of induration. The gain of chromosome 9 in all spermatocytic seminomas appears to be a nonrandom chromosome imbalance {2234}. There is no familial Differential diagnosis The primary differential diagnosis is sarcomatous transformation of a testicular germ cell tumour {2665}. before the germ cells populate the gonadal ridges. Small cells have been reported to be diploid or near diploid by cytophotometry {2555}. Prognosis Only one documented case of metastatic pure spermatocytic seminoma has been reported {1646}. Tumour spread and prognosis The sarcomatous component metastasizes widely. the intermediate cells have intermediate values and the giant tumour cells up to 42C. is most frequently classified as typical seminoma or lymphoma.

which had been traumatized but did not appropriately resolve. or they may be hyperchromatic.0 cm. It may contain occasional fibrous septae and ill defined cysts or clefts {1201. Local extension into the rete testis and epididymis or even beyond is not uncommon. They are large.28 Spermatocytic seminoma with sarcoma. They are indistinguishable from mixed germ cell tumours. undifferentiated. 1649 . vival of one year. A painless swelling is the commonest clini- cal feature. Macroscopy Embryonal carcinoma causes a slight or moderate enlargement of the testis often with distortion of the testicular contour. they are more prone to present with testicular pain. B Sarcomatous component of spermatocytic seminoma. often blending imperceptibly into the adjacent parenchyma. Histopathology The growth pattern varies from solid and syncytial to papillary with or without stromal fibrovascular cores. It may be found in a testis. One or more large irregular nucleoli are present and the nuclear membranes are distinct. of epithelial appearance and not unlike the cells that form the inner cell mass of the very early embryo. A Spermatocytic seminoma associated with sarcoma. Cut section: irregular. grey or whitish to pink or tan often with foci of haemorrhage and necrosis. ICD-O code 9070/3 Synonym Malignant teratoma.2664}. vaguely multinodular.2646}. The cytoplasm is abundant. polygonal or sometimes columnar with large irregular nuclei that usually are vesicular with a see through appearance. variegated white to tan surface with foci of hemorrhage. The tumour cells are undifferentiated. spindle shaped tumour cells. Mitotic figures are frequent. Imaging Embryonal carcinoma is often smaller than seminoma at the time of presentation and more heterogeneous and ill defined. The cell borders are indistinct and the cells often tend to crowd with nuclei abutting or overlapping. Epidemiology Embryonal carcinoma occurs in pure form and as a tumour component in germ cell tumours of more than one histologic type (mixed germ cell tumours). C A sarcoma component that consists of a storiform pattern of undifferentiated. Fig.783. usually finely granular but may also be more or less clear.29 Spermatocytic seminoma. which may mimic torsion. 4. Clinical features Signs and symptoms It occurs first at puberty and has a peak incidence around 30 years of age. In pure form embryonal carcinoma comprises only 2-10% while it occurs as a component in more than 80% of mixed germ cell tumours {1808}. The tumour tissue is soft and granular. 236 Tumours of the testis and paratesticular tissue . Systemic therapy has no effect {347. The average diameter at presentation is 4. focally fibrotic. Some patients present with symptoms referable to metastases and/or gynaecomastia. 4. It bulges extensively from the cut surface and is often not well demarcated from the surrounding testicular tissue. which is approximately 10 years before the peak incidence of classical seminoma. though because of their propensity to grow faster than seminoma. Only two have survived more than a year without disease. It stains from basophilic to amphophilic to eosinophilic. includ- Embryonal carcinoma Definition A tumour composed of undifferentiated A B C Fig.cells of epithelial appearance with abundant clear to granular cytoplasm and a variety of growth patterns. forming clefts or gland-like structures. The tunica albuginea may be invaded and the borders of the tumour are less distinct.

infants and young children and postpubertal males.ic examination of representative sections from the tumour including all growth patterns. Differential diagnoses Differential diagnoses include. and sometimes calcified. and/or tumours with vascular/lymphatic invasion and advanced local stage {1803. Prognosis The most important prognostic factor is clinical tumour stage. microscop- Synonym Endodermal sinus tumour. usually associated with surface implants of similar cells should be considered artefactual. Patients with pure embryonal carcinoma and with vascular invasion tend to have higher stage disease {1200}. B Positive staining for AFP in scattered cells of embryonal carcinoma. Epidemiology In the testis yolk sac tumour (YST) is seen in two distinct age groups. and choriocarcinoma.1198}. which may be present in the tumour. Native Americans. but not in the embryonal carcinoma cells and the same applies to pregnancy specific ß1 glycoprotein (SP1) {1807}. It is less common in Blacks. Loose. In children. 4. Cytokeratins of various classes are present while epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) and vimentin can usually not be demonstrated {1894}. allantois and extra embryonic mesenchyme. In general. embryonal carcinoma unassociated with teratoma. Eosinophils are rarely present as is granulomatous reaction.31 Embryonal carcinoma. This is emphasized by studies defining high risk patients as those with pure embryonal carcinoma. heterogeneous mass (arrows). Human placental lactogen (HPL) is occasionally found focally in the tumour cells {1198. Many embryonal carcinomas are strongly positive for TP53 in up to 50% of the tumour cells {2667}. ICD-O code 9071/3 Ultrastructure Ultrastructural examinations have not proven to be diagnostically useful although it may differentiate embryonal carcinoma from seminoma and glandular like pattern of embryonal carcinoma from somatic type adenocarcinomas. smudged or apoptotic resulting in a biphasic pattern that may mimic choriocarcinoma. orchioblastoma. and in Indians {490. Cells at the periphery of the solid tumour formations may appear degenerated. solid type of yolk sac tumour. Yolk sac tumour Definition A tumour characterized by numerous patterns that recapitulate the yolk sac. irregular. ing abnormal forms. and a small panel of immunohistochemical stains yields the correct diagnosis in the majority of the cases. 4. ing {1615}. Syncytiotrophoblastic cells may occur scattered among the tumour cells as single cells or in small cell groups. the tumour spread is lymphatic. A Positive staining for CD30 in embryonal carcinoma. malignant Sertoli cell tumour and metastases are considerations. more or less cellular and with or without lymphocytic infiltration. predominant embryonal carcinoma. and is often more or less necrotic.1817}. Immunoprofile Embryonal carcinoma contains a number of immunohistochemical markers reflecting embryonic histogenesis but the majority have hitherto not been very useful diagnostically. "floating" tumour cells in vascular spaces. first to the retroperitoneal lymph nodes and subsequently to the mediastinum. In the surrounding tissue vascular and lymphatic invasion are also common and should be carefully distinguished from the intratubular occurrence and from artificial implantation of tumour cells into vascular spaces during handling of the specimen. The age of the patient. Transverse ultrasound image of the testis (cursors) shows an ill defined. it is the most common testicular neoplasm {1274} and occurs in all races. The stroma that varies from scant within the solid formations.1807}. In the adjacent testicular tissue intratubular embryonal carcinoma is often present. among the germ cell tumours. The tumour is fleshy and has foci of haemorrhage and necrosis. AFP may occur in scattered cells {1196. 4. Fig. Among other tumours anaplastic large cell lymphoma.30 Embryonal carcinoma.32 Embryonal carcinoma. to more abundant at the periphery of the tumour is usual fibrous. Germ cell tumours 237 . Haematogeneous spread to the lung may also be seen. Placental alkaline phosphatase (PLAP) occurs focally as a membranous and/or cytoplasmic stain- A B Fig. HCG occurs in the syncytiotrophoblastic cells. seminoma. CD30 can be demonstrated in many cases {2202}. Fig.

1274}.2564}. Several different patterns are usually admixed. it usually occurs as a component of a mixed germ cell tumour and is seen in approximately 40% of NSGCTs. 4.35 Embryonal carcinoma. A Embryonal carcinoma composed of blastocyst-like vesicles. Alpha fetoprotein levels are elevated in 90 percent of cases {1274. 1490} and may be more common in Orientals when compared to Caucasians {1276}. Although it is not clear if retroperitoneal nodes are also involved in those cases. 4. 238 Tumours of the testis and paratesticular tissue . A B Fig. In children there appears to be a predilection for haematogenous spread. Clinical features Signs and symptoms In children. In adults. B Intratubular embryonal carcinoma. Almost ninety percent of cases present with an otherwise asymptomatic scrotal mass {1274}. Seven percent of cases present with a history of trauma or acute onset pain and 1 percent present with a hydrocele {1274}. In adults. There is a right sided preponderance {1274}. soft. although not infrequently one pattern may predominate {1201}. Large tumours show haemorrhage and necrosis {2564}. Histopathology The histopathological appearance is the same.2244}. Fig.34 Embryonal carcinoma. in adults.A B Fig. Macroscopy Macroscopically pure yolk sac tumours are solid. 2595}. Note the tumour necrosis. A Papillary type of embryonal carcinoma. Tumours composed entirely of a single histologic pattern are rare {2564}. 1274}. In 20-26 percent of cases the first site of clinical involvement is the lungs {326.33 Embryonal carcinoma. 40% presenting with haematogenous spread alone {326}. the median age at the presentation is 16-17 months but may extend to 11 years {1274.2244}. it is much more common in Caucasians than in other races. Tumour spread Ten to twenty percent of children have metastases at presentation {1274. Ultrasound examination reveals a solid intratesticular lesion with a different echo texture from that of the testis. Vascular invasion of embryonal carcinoma. The nodal spread is to the retroperitoneum {1274. B Solid type of embryonal carcinoma. and may be present in equal amounts. 1274. The age incidence corresponds to the age incidence of testicular malignant mixed germ cell tumours {2564}. 4. and the cut surface is typically pale grey or grey-white and somewhat gelatinous or mucoid {1021.2078}. regardless of patient age {1021. the pattern of spread is similar to that seen in other NSGCTs.

Hepatoid pattern Collections of hepatoid cells are present in some tumours. Sometimes the vesicles are small and adhere to each other. The nuclei vary in size.37 Yolk sac tumour. The glandlike spaces or clefts form a meshwork of cavities and channels. The connective tissue cores vary from loose and oedematous to fibrous and hyalinized. Glandular-alveolar pattern This pattern consists of collections of irregular alveoli. or separated by other histologic patterns. be hourglass shaped {2593}. It is often associated with a peripheral microcystic pattern which helps distinguish it from typical seminoma and embryonal carcinoma. The tumour cells are small and may be compressed by the vacuoles. Enteric pattern Individual or collections of immature glands are not uncommon {1201. This pattern is uncommon. Negative staining does not exclude a diagnosis of YST.2669}. Sometimes there may be considerable deposits of hyaline material forming wider and more solid brightly eosinophilic and amorphous papillae. They may be adjacent to each other. and usually showing brisk mitotic activity. These structures. Immunoprofile Positive staining for AFP is helpful in diagnosis but the reaction is variable and sometimes weak. strands or collections of individual cells showing prominent nuclei and mitotic activity {1201}. Hyaline globules are frequently seen {1197. enteric or endometrioid glands. Hyaline globules are often present {1201. sometimes interspersed with myxomatous tissue.2669}. The vesicles are lined by columnar to flattened cells.36 Yolk sac tumour in the testis of a one year old. 4. Myxomatous pattern This pattern consists of collections of myxomatous tissue containing sparse cords. They usually resemble allantois. . but the association with other yolk sac tumour patterns and absence of a muscular component aid in their distinction. but generally are small. gland-like spaces and tubular structures lined by cells varying from flattened to cuboidal or polygonal. Endodermal sinus pattern This pattern consists of structures composed of a stalk of connective tissue containing a thin walled blood vessel and lined on the surface by a layer of cuboidal cells with clear cytoplasm and prominent nuclei. Papillary pattern This pattern has numerous. Mitotic activity is typically brisk. and some may Fig. Their absence does not preclude the diagnosis. They are similar to some glands in teratomas. Macrocystic pattern The macrocystic pattern consists of collections of thin-walled spaces of varying sizes. YST shows strong positive immunocyto- A B Germ cell tumours 239 Fig. Mitotic activity is usually present and may be brisk. Polyvesicular vitelline pattern This pattern consists of collections of vesicles or cysts varying in shape and size surrounded by connective tissue which may vary from cellular and oedematous to dense and fibrous. usually fine papillae consisting of connective tissue cores lined by cells with prominent nuclei and often showing brisk mitotic activity. Solid pattern The solid pattern consists of nodular collections or aggregates of medium sized polygonal tumour cells with clear cytoplasm. Hyaline globules may be present and numerous. A Microcystic pattern of yolk sac tumour.Histologic patterns Microcystic or reticular pattern The microcystic pattern consists of a meshwork of vacuolated cells producing a honeycomb appearance.2593}. They are seen scattered within the tumour in varying numbers. Sometimes. and is more frequently seen in tumours from postpubertal patients. are considered a hallmark of YST {2593}. collections of such cells may be numerous and of considerable size. B Glandular-alveolar pattern of yolk sac tumour. although usually they are small. also known as Schiller-Duval bodies. Sometimes the cells may show greater pleomorphism and giant cells may be present. 4. This pattern is the most common one. prominent nuclei. which may contain pale eosinophilic secretion.

and 20. B Endodermal sinus structure (Schiller-Duval body). cytotrophoblastic. is approximately 0.39 Yolk sac tumour. However. and the complete chromosome 22 {1792. has been demonstrated in one tumour. albumin. and others. occurring either as a pure tumour or as a component of a mixed germ cell tumour. the long arm of chromosome 6. loss of 6q also seems to be a recurrent change. B Enteric pattern. including loss of the short arm of chromosome 1 (in particular the p36 region). 4. Other proteins present in fetal liver such as alpha-1 antitrypsin. B 240 Tumours of the testis and paratesticular tissue . there are no established morphologic prognostic criteria. Prognosis and predictive factors Clinical criteria Age does not appear to be prognostically important {1274.2595}. Morphologic criteria Except for lymphovascular invasion. ferritin. The yolk sac tumours of adults. and gain of the long arm of chromosomes 1. Clinical stage and degree of AFP elevation are of prognostic value {1274. being a pure or a part of a mixed TGCTs are also aneuploid B {1543}.19%) of testicular germ cell tumours.A chemical staining with low molecular weight cytokeratin. ICD-O codes Choriocarcinoma 9100/3 Trophoblastic neoplasms other than choriocarcinoma Monophasic choriocarcinoma Placental site trophoblastic tumour 9104/1 Epidemiology Pure choriocarcinoma represents less than 1% (0. which might indicate that it is related to the histology of the tumour.000 male population in those countries with the highest frequency of testicular cancer.2244. and intermediate trophoblastic cells.8 cases per year per 100.2244}.2054. no gene or genes involved in the yolk sac tumour of neonates and infants have been identified yet. Interestingly. Fig.38 Yolk sac tumour. Genetics Recurrent anomalies have been detected in the infantile yolk sac tumours of the testis. choriocarcinoma is admixed with other germ cell tumour elements in 8% of testicular germ cell tumours {1382}. plasm composed of syncytiotrophoblastic. A Hepatoid pattern. A Endodermal sinus pattern. Trophoblastic tumours Choriocarcinoma Definition Choriocarcinoma is a malignant neo- A Fig. and to a lesser extent the 17q12-q21 region. High level amplification of the 12q13-q14 region (of which MDM2 might be the target). Its estimated incidence.2693}. may also be present {1201}. 4.

Clinical examination of the testes may or may not disclose a mass. central nervous system dysfunction. of syncytiotrophoblastic. which is almost isoechoic compared to the normal parenchyma (arrow). although some patients with visceral metastases may lack lymph node involvement. Occasional patients develop hyperthyroidism because of the cross reactivity of hCG with thyroid stimulating hormone. A Macroscopy Choriocarcinoma most commonly presents as a haemorrhagic nodule that may B Fig. In occasional cases. The syncytiotrophoblastic cells are usually multinucleated with deeply staining. leaving a marked preponderance of cytotrophoblastic and intermediate trophoblastic cells. They often Imaging Choriocarcinomas do not have distinctive imaging characteristics to differentiate them from other non-seminomatous tumours. autopsy studies have shown common involvement of the lungs (100%). Additionally. which have been descriptively termed "monophasic" {2672}. A Longitudinal ultrasound image of the testis shows a small. Retroperitoneal lymph nodes are commonly involved. 4. This is because the primary site may be quite small. irregularly shaped.A B Fig. A Pleomorphic cell type. AFP positive staining. Most commonly. Histopathology Choriocarcinoma has an admixture. hypotension. Patients typically have very high levels of circulating human chorionic gonadotropin (hCG) (commonly greater than 100. and adrenal glands (56%) {1800}. brain. hyperchromatic and often smudged appearing nuclei. eosinophilic to amphophilic cytoplasm.40 Yolk sac tumour. usually at the periphery of a nodule that has a central zone of haemorrhage and necrosis. In some cases with marked regression. They most commonly present with symptoms referable to metastases. they typically have several. they are admixed in a more or less random fashion. usually in an extensively haemorrhagic and necrotic background. Germ cell tumours 241 . 4. the consequent Leydig cell hyperplasia causes some patients (about 10%) to present with gynecomastia. be surrounded by a discernible rim of white to tan tumour.000 mIU/ml). despite widespread metastatic involvement. Clinical features Signs and symptoms Patients with choriocarcinoma are young. and anaemia. Haemorrhage in multiple visceral sites represents the hallmark of a “choriocarcinoma syndrome” {1529}. The patient presented with hemoptysis. melena. B Polyvesicular vitelline pattern. in varying proportions. and spleen. Their appearance varies from hypoechoic to hyperechoic. large. a white/grey scar is the only identifiable abnormality. Because of the cross reactivity of hCG with luteinizing hormone. the syncytiotrophoblasts "cap" nests of cytotrophoblasts in a pattern that is reminiscent of the architecture seen in immature placental villi.42 Choriocarcinoma. The haematogenous distribution of metastases explains the common presenting symptoms: haemoptysis.41 Yolk sac tumour. Blood vessel invasion is commonly identified in all of the patterns. These cellular components are arranged in varying patterns. Tumour spread Choriocarcinoma disseminates by both haematogenous and lymphatic pathways. cytotrophoblastic and intermediate trophoblastic cells. the syncytiotrophoblastic cell component is inconspicuous. dyspnoea. averaging 25-30 years of age. In some examples. gastrointestinal tract (71%). haematemesis. Fig. They may invade the tunica albuginea. liver (86%). slightly heterogeneous mass. 4. B Chest radiograph shows multiple lung metastases. or even totally regressed.

they are larger than cytotrophoblastic cells but may not be readily discernible from them without the use of immunohistochemical stains. Intermediate trophoblastic cells have eosinophilic to clear cytoplasm and single nuclei. 1616} and. As a consequence.have cytoplasmic lacunae that contain pink secretion or erythrocytes. Follow-up was uneventful after orchiectomy in both cases {2672}. Mononucleated intermediate trophoblasts with eosinophilic cytoplasm. Syncytiotrophoblastic cells with deeply eosinophilic cytoplasm and multiple. This "monophasic" example has only rare multinucleated syncytiotrophoblastic cells and consists mostly of mononucleated cytotrophoblastic and intermediate trophoblastic cells. likely reflecting a greater tumour burden {7.281.43 A Choriocarcinoma with typical hemorrhagic appearance. The latter consisted of eosinophilic mononucleated angioinvasive cells that were diffusely immunoreactive for placental lactogen and focally for chorionic gonadotrophin. 4. they "cap" aggregates of mononucleated trophoblastic cells with pale to clear cytoplasm. smudged appearing nuclei. A favourable lesion described as cystic trophoblastic tumour has been observed in retroperitoneal metastases after chemotherapy in eighteen patients.2042} and epithelial membrane antigen {1894}. B Choriocarcinoma. Prognosis Choriocarcinoma often disseminates prior to its discovery. Stains for hCG may also highlight large cells that possibly represent transitional forms between mononucleated trophoblastic cells and syncytiotrophoblasts. The intermediate trophoblastic cells are positive for human placental lactogen {1615.1897}. alpha subunit of inhibin {1664. small foci having a similar appearance may rarely be seen in the testis of patients with germ cell tumours who have not received chemotherapy. Trophoblastic neoplasms other than choriocarcinoma Two cases have been described of trophoblastic testicular tumours that lacked the biphasic pattern of choriocarcinoma and were composed predominantly of cytotrophoblastic cells (monophasic choriocarcinoma) or intermediate trophoblastic cells (similar to placental site trophoblastic tumour). Positive HCG staining. worse prognosis. Note the fibrin aggregates.575. B Placental site trophoblastic tumour. high levels of hCG correlate with a C D Fig.44 A Choriocarcinoma. the majority of patients present with advanced stage disease. would be expected to stain for Mel-CAM and HLA-G {2425}. The cytotrophoblastic cells have pale to clear cytoplasm with a single. and placental alkaline phosphatase shows patchy reactivity in about one half of the cases. C Choriocarcinoma. A B Immunoprofile The syncytiotrophoblasts are positive for hCG. Additionally. probably because of its propensity to invade blood vessels. 4. The lesions consist of small cysts lined predominantly by A B Fig. D Choriocarcinoma. It is this aspect of choriocarcinoma that causes it to be associated with a worse prognosis than most other forms of testicular germ cell tumour. All of the cell types express cytokeratin. irregularly shaped nucleus with one or two prominent nucleoli. if comparable to the gestational examples. 242 Tumours of the testis and paratesticular tissue .

Fetal type tissue may also consist of ectodermal. In adults. Thyroid tissue has rarely been observed {2792}. mesoderm and ectoderm). the frequency of pure teratoma ranges from 2. 4. most are seen in young adults. Tumours consisting of ectoderm. Occasionally. teratoma differentiated (mature). similar tumours found after puberty are known to metastasize. respiratory. Most patients present with a mass that is usually firm. embryonal carcinoma. struma testis. serum levels of AFP and hCG may be elevated in adult patients {1211}. Macroscopy The tumours are nodular and firm. calcification. or endoderm only are classified as monodermal teratomas e. which result in variable degrees of shadowing. mature tissue types consist of keratinizing and nonkeratinizing squamous epithelium. A number of congenital abnormalities. mesoderm. particularly in children such as skin. Clinical features Signs and symptoms In children. It has been recommended to consider these morphologies as a single entity based on genetics. yolk sac tumour or choriocarcinoma is classified as teratomatous component. 330. Teratomas in children and the dermoid cyst are benign. nontender and does not transilluminate.scribed complex masses. Focal reactivity for hCG is found {427}. Cartilage.2753}. Symptoms consist of swelling or are due to metastases. The cut surfaces are heterogeneous with solid and cystic areas corresponding to the tissue types present histologically. They can have an organoid arrangement resembling primitive renal or pulmonary tissues. The mass may be hypoechoic but the laminations often give rise to an “onion-skin” or “target” appearance {813. Of the mesodermal components. ICD-O codes Teratoma Dermoid cyst Monodermal teratoma Teratoma with somatic type malignancies Epidemiology Teratoma occurs in two age groups.2482}. Virtually any other tissue type can be seen. The capsule of the lesion is well defined and is sometimes calcified. mature tissues or have immature.2264}. 65% of teratomas occur in the 1st and 2nd year of life with a mean age of 20 months. gastrointestinal and genitourinary tract. In the prepubertal testis.813}. Teratomas Definition A tumour composed of several types of tissue representing different germinal layers (endoderm. mitotic figures are infrequent. Conversely. immature teratoma. mononucleated trophoblastic cells with abundant eosinophilic cytoplasm. precocious puberty is not seen. Teratoma may contain syncytiotrophoblastic giant cells. the presence of IGCNU is not proven. In postpubertal patients. In children.45 Cystic trophoblastic tumour. They may be composed exclusively of well differentiated. Histopathology The well differentiated. The cyst is lined by relatively inactive appearing mononucleated trophoblastic cells.2264. Cartilage. fibrosis. The nuclei often have smudged chromatin. teratoma differentiated (immature). Cyst formation is commonly seen in teratomas and the demonstration of a predominately cystic mass suggests that it is either a teratoma or a mixed germ cell tumour with a large component of teratoma within it. Teratomas and other malignant tumours may have a similar appearance and great care should be taken in evaluating the mass for any irregular borders. bone and pigmented areas may be recognizable.2377}.2805}. Epidermoid cyst The distinctive laminated morphology is reflected in ultrasound images.g. and scar formation result in echogenic foci. Organoid structures are not uncommon. It can be difficult to differentiate fetal-type tissues from teratoma with somatic type maligGerm cell tumours 243 9080/3 9084/0 9084/3 Synonyms Mature teratoma. Serum alpha-fetoprotein (AFP) levels are helpful in the differentiation of teratomas from yolk sac tumours {924. Approximately 2-3% of prepubertal testis tumours may be associated with or misdiagnosed as a hydrocele. particularly if the tumour contains a cystic component.1807} and 4750% in mixed TGCTs {172. the incidence is between 24-36% {326.7-7% {804.2366}. endodermal and/or mesenchymal tissues. Imaging Teratoma Teratomas are generally well circum- . They are sharply marginated. Fig.2664}. round to slightly oval masses. Since neither of these tumours is hormonally active. A single type of differentiated tissue associated with seminoma. neural and glandular tissues. which would suggest a malignant lesion {671. fetal-like tissues. irregular or nodular. predominantly of the GU tract have been observed {883. because the markers used are not specific at this period of life for IGCNU {1617. Tumour spread Metastatic spread from teratomas in prepubertal children is not reported {326. muscular tissue is the most common {548}.

ICD-O code 9084/0 Immunoprofile The differentiated elements express the immunophenotype expected for that specific cell type. Testicular dermoid cyst is a specialized.1198. 4. as well as CGH.349. pure cartilagenous teratoma {2427}. Multiple concentric rings are visualized giving an "onion-skin" appearance.48 A Teratoma. hCG can be seen in syncytiotrophoblastic cells. Teratoma may metastasize as such {793.1966. Some have classified foci indistinguishable from primitive neuroectodermal tumours as malignant irrespective of size {1797} whereas others recognize a nodule equal to or greater than a (4x objective) microscopic field as PNET {1722}. hypoechoic.2670}. Other markers include alpha-1 antitrypsin. oval mass (arrow). and possibly epidermal (epidermoid) cyst.2413}. the metastatic frequency is 66%. has failed to demonstrate chromosomal changes in these tumours [{1792.A B Fig. 1392. Epidermoid cysts lack skin appendages. teratoma is hypotriploid in adult patients {1763. In the prepubertal testis. If it is associated with a scar (burned out component). Teratoma shows mostly synchronous metastases. Genetics Teratomas of the infantile testis are diploid {1350. in 13% of cases. benign form of cystic teratoma that is analogous to the common ovarian tumour {2670}.324. In a series from Indiana. 37% of 41 adult patients with pure teratoma showed synchronous metastases {1471}. teratomas as part of TGCTs have similar genetic changes compared to other components. it is metachronous {1806}.1609. Most have been in young men who presented with testicular masses. Prognosis The behaviour of teratoma in the two different age groups is strikingly different.629. between chromosome 12 and 15 as found in a family with a predisposition to sacral teratoma at young age {2724} is involved in the genesis of this type of tumour.976.1615. but an occasional example has 244 Tumours of the testis and paratesticular tissue . cystic mass. Teratoma can show invasion of paratesticular tissue and intra and extratesticular vascular invasion. even after microdissection of the tumour cells. It is rare.46 Teratoma.2209}. In contrast to the diploidy of teratomas of neonates and infants. The cellular composition of metastases may differ from that of the respective primary tumour {548}. Monodermal teratomas have been described as struma testis {2427}. Alpha-fetoprotein pro- A B Fig.1204.47 Epidermoid cyst. duction occurs in about 19-36% of teratomas in intestinal and hepatoid areas {1196. with less than 20 cases reported {126. A Longitudinal ultrasound image of the left testis (cursors) shows the normal parenchyma being replaced by complex. Karyotyping. with or without small areas of other teratomatous elements. 2128. despite appearance. Note the laminated structure. nancies. B Teratoma. teratoma is benign {2264}. or in some instances precursor cells may invade vascular spaces and differentiate at the metastatic site {1800}. A Transverse ultrasound image through the lower pole of the testis shows a well marginated. PLAP is also demonstrable in glandular structures {346. multiseptated.1807}.2054} for review].1963. In addition.2509}. are hypotriploid {1542}. the fully differentiated tumour cells found in residual teratomas as a remainder after chemotherapy of a non-seminoma of adults. 4. In fact. CEA and ferritin {1198}. It remains to be shown whether the recently identified constitutional translocation Dermoid cyst Definition A mature teratoma with a predominance of one or more cysts lined by keratinizing squamous epithelium with skin appendages. B Gross specimen confirms the cystic nature of the mass. A B Fig. 4. Carcinoid tumour within the testis. B Epidermoid cyst within the stroma of the testis. teratoma shows metastases in 22-37% of cases. In the postpubertal testis.2658}. 1807.

ecto. intestinal tis- sue.) Primitive neuroectodermal tumour has been described {38. thyroid. and it may contain hair and “cheesy”.1903. fat.or mesoderm. sarcomas and carcinomas. Fig. Pure cartilaginous teratoma has been described {2427}. salivary gland and pancreatic tissue. Epidermoid cysts have been considered as a tumour like lesion. On gross examination a single cyst is usually seen. Only PNET occurring in the metastasis is associated with a poor prognosis {1722}. Many examples also have an associated lipogranulomatous reaction in the parenchyma. recently we have encountered an epidermal cyst with diffuse intratubular malignant germ cells indicating that some may be teratomatous. They are seen in 3-6% of patients with metastatic GCTs {484}. ICD-O code 9084/3 Monodermal teratomas Definition A tumour that consists of only one of the three germ layers (endo-. gastric epithelium.49 Teratoma. However. The histology is similar to that in other sites.1909. C Teratoma with scar formation. Patients are well on follow-up.g. bundles of smooth muscle. bone.50 Teratoma with vascular invasion. Clinical features Nongerm cell malignant tumours may arise in primary or metastatic germ cell tumours (GCTs) and are most likely derived from teratomas {1720}.A B C D Fig. 4. The seminiferous tubules usually have normal spermatogenesis and always lack intratubular germ cell neoplasia. D Carcinoid tumour within teratoma. Teratoma with somatic-type malignancies Definition A teratoma containing a malignant component of a type typically encountered in other organs and tissues. keratinous material. 4. cartilage. On microscopic examination a keratin filled cyst is lined by stratified squamous epithelium with associated pilosebaceous units as normally seen in the skin. B Teratoma with various types of immature tissue. glands having ciliated or goblet cell containing epithelium. Germ cell tumours 245 . all having bland cytological features.2904} either in pure form or as a component of a mixed germ cell tumour. A surrounding fibrous wall may also contain sweat glands. occurred in a child. A Teratoma with various types of mature tissue. e.

they may resemble neuroblastoma. The most common type of somatic type malignancy seen in patients with testicular GCTs is sarcoma {39. Signs of metastatic disease include abdominal mass. haemorrhage and necrosis.1763.A B C Fig. 2597. Mixed germ cell tumours are rarely seen in prepubertal children. without seminoma. combined tumour is synonymous for seminoma and any other cell type and malignant teratoma trophoblas- 246 Tumours of the testis and paratesticular tissue .51 A Cut surface of dermoid cyst. peripheral neuroepithelioma or ependymoblastoma. spermatic cord on the right. including chondrosarcoma.2665.1282. How much expansile growth is required has not been clearly defined. the prognosis is not affected {40. GFAP and HBA. 4.1722.2200. With seminoma. Therapy designed for the specific type of somatic neoplasm may also be helpful. Cystic spaces indicate teratomatous elements. AFP and HCG are negative. but some authors have suggested that the tumour should fill a 4X field of view {2668}.1815}.1815. 2363}.1815. Those with foci of choriocarcinoma or numerous syncytiotrophoblastic cells tend to involve liver and/or brain.40. the age is the same as pure nonseminoma.71. surgical resection is the treatment of choice. tic for choriocarcinoma and non-seminomatous germ cell tumour types. Serum elevations of AFP and hCG are common {2265}.2665}. Tumours of more than one histological type (mixed forms) Definition This category includes germ cell tumours composed of two or more types.1720.1909. Nephroblastoma like teratomas are rare in the testis {881}. ICD-O codes Tumours of more than one histological type (mixed forms) 9085/3 Others Polyembryoma 9072/3 Synonyms Malignant teratoma intermediate includes only teratoma and embryonal carcinoma.2666}. gastrointestinal tract disturbances or pulmonary discomfort. 484. B Dermoid cyst with a stratified squamous epithelial lining and pilosebaceous units and smooth muscle bundles in its wall. the nongerm cell tumour has demonstrated the i(12p) chromosomal abnormality associated with GCTs.1334. the frequency of mixed germ cell tumours has been reported between 32-54% of all germ cell tumours {1195. EMA and some- times CEA. the somatic type malignancies have a poor prognosis {1525. Any type of sarcoma may occur in germ cell tumours. Tumour spread The tumours follow the usual route through retroperitoneal lymph nodes to visceral organs. Incidence Excluding seminoma with syncytiotrophoblastic cells and spermatocytic seminoma with sarcoma. Patients present with painless or painful testicular swelling.1815}. About half are undifferentiated sarcomas and most of the remainder display striated or smooth muscle differentiation. Prognosis If the malignant tumour is limited to the testis. some have demonstrated chromosomal rearrangements characteristic of the somatic tumour in conventional locations {1815}. They do not respond to germ cell tumour chemotherapy. One third is chromogranin-positive. Care must be taken not to confuse chemotherapy induced atypia with the development of a secondary malignancy. In metastatic sites. but are more common in metastases {1721}. medulloepithelioma.1815. Clinical features Signs and symptoms The age range of these tumours depends on whether or not they contain seminoma. Stains for PLAP. squamous carcinomas and neuroendocrine carcinomas have all been reported {40. Carcinomas are less often associated with GCTs.1723.484. Macroscopy The enlarged testis shows a heterogeneous cut surface with solid areas. malignant fibrous histiocytoma and malignant nerve sheath tumours. the age is intermediate between that of seminoma and pure non-seminoma. Primitive neuroectodermal tumours (PNETs) have been increasingly recognized {38. Somatic genetics In several cases. osteosarcoma. C Epidermoid cyst with laminated keratin in the lumen and at the periphery atrophic seminiferus tubule without intratubuler germ cell neoplasia.1807}. Most are cytokeratin-positive and stain with synaptophysin and Leu 7. These tumours stain for cytokeratins.998. Tumours may also stain with antibodies to S-100 protein. Histopathology Nongerm cell malignant tumours are characterized by an invasive or solid (expansile) proliferation of highly atypical somatic cells that overgrow the surrounding GCT. Adenocarcinomas.

teratoma and syncytiotrophoblastic cells {1796}. 4. 3) Residual teratoma is often cystic and may show reactive cellular pleomorphism or frank malignant change with or without selective overgrowth. 1) Necrosis is often associated with ghost- Burned out germ cell tumour Occasionally. suggest that these should be regarded as mixed germ cell tumours with a unique growth pattern. in one series.350. syncytiotrophoblastic cells and teratoma. The tumour is composed of small round blue cells with rosettes. 40% of mixed germ cell tumours contain varying numbers of syncytiotrophoblastic cells {1796}. the individual components consisting of embryonal carcinoma. A B Fig. 4) Viable tumour may show loss of marker production e. The scar is frequently associated with haematoxylin staining bodies that contain not only calcium but also DNA {144}. is considered by some as a unique germ cell tumour and is listed under one histologic type {1805}. The latter is frequently overlooked {2367}. like necrotic tumour cells surrounded by a xanthogranulomatous response. A Adenocarcinoma in patient with testicular GCT. was teratoma and embryonal carcinoma {1195} and in another. In embryonal carcinoma. The scar can be associated with intratubular malignant germ cells or residual viable tumour such as teratoma Germ cell tumours 247 .144. Cells with abundant eosinophilic cytoplasm are rhabdomyoblasts. 2) Fibrosis may show cellular pleomorphism. respectively {2367}. Embryonal carcinoma and teratoma are each present in 47% of cases and yolk sac tumours in 41%. 90 and 83% of these tumours. The most common combination. However. The diagnosis should include all components that are present and the quantity of each should be estimated. yolk sac tumour. particularly choriocarcinoma {1556. The tumour displays an organoid pattern with mitoses. B PNET in a GCT patient.A B Fig.2663}. 4.53 Teratoma with somatic type malignancies.52 Teratoma with somatic type malignancies. While the basic germ cell tumour types are infrequent in pure forms they are very frequent in the mixed forms. {730. teratoma and yolk sac tumour the metastases are identical to the primaries in 95. B Rhabdomyosarcoma in a GCT patient. the combination of embryonal carcinoma. 1868} a rare germ cell tumour composed predominantly of embryoid bodies. germ cell tumours of the testis. Treatment effect Radiation and chemotherapy may produce the following histologic changes.g. AFP or hCG {1797. yolk sac tumour.2252} can completely or partially undergo necrosis and regress {20. 145. A Neuroendocrine carcinoma arising in a GCT patient. The histology of the metastases reflects that of the primary tumour in about 88% of cases. Histopathology The various types of germ cell tumour can occur in any combination and their appearances are identical to those occurring in pure form. Polyembryoma.556} leaving a homogeneous scar. Goblet cells and glands are present in desmoplastic stroma.

Genetics A vast amount of knowledge has been accumulated concerning the genetic features of mixed germ cell tumours. Gross specimen showing a tumour with cystic areas. Fig.1817. Prognosis Clinical criteria Mixed germ cell tumours containing large areas of seminoma appear to respond better to treatment than those with no or only microscopic foci of seminoma. There is a strong correlation between elevated serum levels of AFP and the presence of YST {1807. hCG and other placental glycoproteins (pregnancy specific ß1 glycoprotein. CD30 immunoreactivity on the right. There is a small amount of normal parenchyma remaining posteriorly (asterisk).2249}. Syncytiotrophoblastic cells either singly or in association with foci of choriocarcinoma are positive for Morphologic criteria Vascular/lymphatic invasion in the primary tumour is predictive of nodal metastasis and relapse {802.Fig. Note seperation of two components: teratoma (left) and embryonal carcinoma (right).556. Fig. 4. human placental lactogen and placental alkaline phosphatase). yolk sac tumour.823.1917}. {262. A B A C D B Fig. teratomatous glands and hepatoid cells. syncytiotrophoblasts. 248 Tumours of the testis and paratesticular tissue .802. earlier in this chapter.2834}.2664}. 4.1087. B Embryonal carcinoma.802. D Mixed seminoma and embryonal carcinoma. In contrast. 4. heterogeneous mass (arrows) with cystic areas (arrowheads).848.58 A.B Mixed germ cell tumour: teratoma and yolk sac tumour. Fig.1817. The presence and percent of embryonal carcinoma in the primary tumour is also predictive of stage II disease {278. Longitudinal ultrasound image of the testis shows a large.55 Mixed germ cell tumour. it is discussed in the genetic overview to germ cell tumours.823.54 Mixed germ cell tumour. Immunoprofile Most tumours show immunoreactivity for AFP in the yolk sac elements. the presence of teratoma and yolk sac tumour is associated with a lower incidence of metastases following orchiectomy in clinical stage I disease {311.56 Teratoma and choriocarcinoma (trophoblastic teratoma).823. The metastases often differ from the residual viable tumour in the testis {167}. 4. 4. C Mixed seminoma and embryonal carcinoma.57 A Mixed teratoma and embryonal carcinoma. 2367}.

A B Fig.60 Mixed germ cell tumour. B Embryonal carcinoma. A Seminoma intimately admixed with teratoma. yolk sac tumour and syncytiotrophoblasts.59 Mixed germ cell tumours. B Polyembryoma. 4. Germ cell tumours 249 . A B Fig. A Embryonal carcinoma and yolk sac tumour. 4.

Leydig cell tumour Definition A tumour composed of elements recapitulating normal development and evolution of Leydig cells.61 Leydig cell tumour. B Leydig cell tumour. Jacobsen M. Note the Reinke crystals. Libido B Fig.1738}. The name given to this group does not indicate a preference for any particular concept of testicular embryogenesis. granulosa cell tumours and tumours of the thecoma/fibroma group. In children. Bilaterality is rare {1318. Damjanov G. Renshaw Sex cord / gonadal stromal tumours. Progesterone. The latter may be associated with low testosterone and follicle stimulating hormone levels {213. Imaging Leydig cell tumours are generally well defined. Unlike germ cell tumours. Some of these tumours occur in androgen insensitivity syndrome (AIS) and adrenogenital syndrome (AGS) and should be classified under tumour-like lesions. it may not be possible on histological grounds to forecast their behaviour.K. Woodward I.2664}. Occasionally. hypoechoic. 4. precocious puberty is not uncommon {2831}. B Tumour cells stain intensely for inhibin. A Fig. almost always in adults. Painless testicular enlargement is the most common presentation.2366}. the aim throughout this section is to closely parallel the WHO terminology and classification of ovarian tumours. There are no sonographic criteria.2831}. Cheville P.A. Synonym Interstitial cell tumour. they constitute about 3% of testis tumours and 14% of stromal tumours {2366}. which can differentiate benign from malignant Leydig cell tumours and orchiectomy is required. particularly testosterone. haemorrhage or necrosis. These tumours constitute about 4-6% of adult testicular tumours and over 30% of testicular tumours in infants and children. Leydig cell tumours are seen in patients with Klinefelter syndrome {1800. Gynecomastia is seen in about 30% of patients either as a presenting feature or at clinical evaluation for a testicular mass {979.63 Leydig cell tumour.Sex cord / gonadal stromal tumours I.1800.62 Leydig cell tumour. Serum estrogen and estradiol levels may be elevated {828}. A Typical morphological appearance. metastasize.J. there is no race predilection {1800}.2052}. which is also present to a lesser extend in adjacent tubules. 4. A Leydig cell tumour with cords of tumour cells.2664}. Paniagua A. The sonographic appearance is quite variable and is indistinguishable from germ cell tumours. However. A B Fig. As with the germ cell tumours. Clinical features Signs and symptoms The tumour is most common in the 3rd to 6th decade and in children between 3 and 9 years {1318. Sertoli cell tumours.A.2664}. Nistal R. pure forms Included in this category are Leydig cell tumours. 4. About 5-10% of patients have a history of cryptorchidism {1318}. In infants and children. androstenedione and dehydroepi-androsterone {298. small solid masses but may show cystic areas. Leydig cell tumours produce steroids. Epidemiology Leydig cell tumours account for 1-3% of testicular tumours {1318. urinary pregnanediol and urinary 17-ketosteroid levels may be elevated {535.1800}. ICD-O codes Leydig cell tumour Malignant Leydig cell tumour 8650/1 8650/3 and potency may be compromized. About 10% of these tumours. 250 Tumours of the testis and paratesticular tissue . Sesterhenn J.

malignant Leydig cell tumours are managed by radical orchiectomy. Reinke crystals can be seen in about 30-40% of cases.g. There may be variation in nuclear size. Most malignant Leydig cell tumours are DNA aneuploid and show increased MIB-1 proliferative activity. There may be hyalinization and calcification. Histopathology The tumour shows variable histologic features recapitulating the evolution of Leydig cells. The stro- ma is usually scant. in contrast to benign Leydig cell tumours that are DNA diploid with low MIB-1 proliferation {445. Differential diagnosis Most importantly. but may be hyalinized and prominent. C Leydig cell tumour with adipose metaplasia. Sex cord / gonadal stromal tumours 251 .2269}. a benign Leydig cell tumour can be aneuploid. S100 protein has also been described {1663}. Mitoses are generally rare.2456}. but may be seen in the nucleus and interstitial tissue. Binucleated or multinucleated cells may be present. Currently. These are usually bilateral. and not expansile growth pattern. The eosinophilic histiocytes of malakoplakia can be identified by the typical cytoplasmic inclusions (Michaelis Gutman bodies) and prominent intratubular involvement. Malignant tumours do not respond to radiation or chemotherapy. the tumours are positive for vimentin and inhibin {218. parallel lines. Ultrastructure The polygonal Reinke crystals can have a variable appearance depending on the plane of sectioning e. insular. Occasionally it is oedematous. Occasionally. various dot patterns. A Leydig cell tumour with lipochrome pigment.1665}. the tumour cells are spindled or have scant cytoplasm. and survival is poor with the majority of patients developing metastases that result in death. Some nuclear atypia can be observed.1666. Macroscopy The tumours are well circumscribed. Psammoma bodies can occur {165. B Unusual microcystic change in Leydig cell tumour. necrosis and vascular invasion {445.1665}. B Note lipomatous change.1727}. dark brown and show cellular pleomorphism and pigmentation and are associated with a hyalinized fibrous stroma {1733. increased mitotic activity.64 Leydig cell tumour. 4.1159. cytologic atypia. 4.2455.1739}. The crystals are usually intracytoplasmic. The cytoplasm may be vacuolated or foamy depending on the lipid content. A B Malignant Leydig cell tumour ICD-O code 8650/3 Fig. Lipofuscin pigment is present in up to 15% of cases. The nuclei are round or oval with a prominent nucleolus. pseudotubular and ribbon-like. but may be trabecular. Leydig cell hyperplasia has an interstitial Approximately 10% of Leydig cell tumours are malignant.1393}.2230. A positive reaction for cytokeratin does not exclude the diagnosis. Leydig cell tumours have to be distinguished from the multinodular tumours of the adrenogenital syndrome. A Note lipid rich cytoplasm. The growth pattern is usually diffuse. The tumour has a rich vascular network as in endocrine tumours. 4. and retroperitoneal lymphadenectomy. On occasion. Malignant features include large size (greater than 5 cm).66 Malignant Leydig cell tumour. The most common type consists of medium to large polygonal cells with abundant eosinophilic cytoplasm and distinct cell borders. The majority of malignant Leydig cell tumours have most or all of these features {445}.A B C Fig. prismatic or hexagonal lattice {1290. Fig. Expansion into paratesticular tissue can be detected in about 10-15% of cases {1318}. Even fatty metaplasia can occur. often encapsulated and 3-5 cm in size.65 Leydig cell tumour. The cut surface is usually homogeneously yellow to mahogany brown. Similar lesions are seen in Nelson syndrome {1234. Immunoprofile In addition to the steroid hormones.1318. Stromal tumours with prominent luteinization can mimic a Leydig cell tumour.

Hormone related symptoms are not typical of Sertoli cell tumours {2894}. These 8642/1 Imaging Sertoli cell tumours are generally hypoechoic. Clinical features Signs and symptoms Patients harbouring Sertoli tumours of any type typically present with a slowly enlarging testicular mass {827}.67 Malignant Leydig cell tumour. The vast majority of Sertoli cell tumours are sporadic.A B C D Fig.68 Sertoli cell tumour. which can often be distinguished. B Pronounced nuclear and cellular pleomorphism. D Leydig cell tumour with spindle change. characteristics are nonspecific and indistinguishable from germ cell tumours. prepubertal or adult Sertoli cells. 4. C Note abnormal mitosis in center. ICD-O codes Sertoli cell tumour Sertoli cell tumour lipid rich variant Sclerosing Sertoli cell tumour Large cell calcifying Sertoli cell tumour Synonym Androblastoma. They can be variable echogenecity and cystic areas. Epidemiology They account for less than 1% of all testicular tumours. are more common in infants and children. 4. and Peutz-Jeghers syndrome {2894}. Sertoli cell tumours in boys with Peutz-Jeghers syndrome have signs of hyperestrinism {61. Sertoli cell tumours NOS are only exceptionally found in men 8640/1 8641/0 under the age of 20 years {2894}. A Necrosis. but some tumours have been associated with genetic syndromes such as androgen insensitivity syndrome {2268}. and the mean age at the time of diagnosis. Variant forms. Carney syndrome {2785}. Intratubular Sertoli cell tumour in a patient with Peutz-Jeghers syndrome. is the large cell calcifying Sertoli cell tumour. is around 45 years. The imaging Fig. Sertoli cell tumour Definition Sertoli cell tumour is a sex cord-stromal tumour of the testis composed of cells expressing to a varying degree features of fetal. Typically Sertoli cell tumours NOS occur in adults. and especially those that occur as parts of various syndromes. An interesting subtype.2907}. 252 Tumours of the testis and paratesticular tissue .

masses can be multiple and bilateral and. Histopathology Tumour cells have oval. Immunoprofile Sertoli cell tumours NOS stain with antibodies to vimentin (90%) and cytokeratins (80%) and to a variable extent with antibodies to inhibin (40%). An increased number of mitotic figures (>5 per HPF) may be found in about 15% of cases. Sertoli cell tumours NOS are always unilateral. Overall the cells appear bland and uniform. and S100 Sex cord / gonadal stromal tumours 253 . The cytoplasm may be pale eosinophilic or clear and vacuolated due to lipids. Mitoses are uncommon and most cases contain fewer than 5 mitoses per ten high power fields. tumour cells may form retiform and tubular-glandular structures.873}. This case was malignant. Minor calcifications can be found in about 10% of cases.Leydig cell hamartomas in androgen insensitivity syndrome (AIS). These tubules may be solid or hollow with a central lumen. Large cell calcified Sertoli cell tumour. Foci of haemorrhage may be seen. and the nucleoli are not overtly prominent. On cross section the tumours appear tan-yellow or greyish white. cords and cell nests is fibrotic and moderately cellular to acellular and hyalinized. Macroscopy Most tumours present as spherical or Fig. Calcifications will app`ear as brightly echogenic foci. are characterized by large areas of calcification which are readily seen by ultrasound {410. The stroma between the tubules.5 cm {2894}. B Sertoli cell hamartoma in center and nodular Leydig cell proliferation. A Sertoli . but in itself this finding should not be considered to be a sign of malignancy. The tumour cells are typically arranged into tubules surrounded by a basement membrane. and some large cell calcifying Sertoli cell tumours on record were also bilateral {1391}. Longitudinal ultrasound image of the testis shows a small well defined mass (arrow). Furthermore. Mild nuclear pleomorphism and atypia is found in a minority of cases. which block the transmission of sound (posterior acoustic shadowing). well circumscribed masses.72 A Large cell calcified Sertoli cell tumour shows bilateral. Inflammatory cells are typically absent. The hyalinized stroma contains often dilated blood vessels and may be markedly oedematous. but even in such neoplasms. brightly echogenic masses with posterior acoustic shadowing (arrow). 4. or elongated nuclei.A B Fig. 4. In some instances the cytoplasm of tumour cells is prominently eosinophilic. 4.69 Androgen insensitivity syndrome. A B Fig. as the name implies. 4. The average size of tumours recorded in the largest series of 60 cases is 3. B Sertoli cell tumour. Some tumours consist predominantly of solid sheets and nodules. It is slightly heterogeneous with small cysts (anechoic areas) within it. note focus of yellow necrosis. but occasional tumours may show more prominent deposits. Fig. Nuclear grooves and inclusions are usually not seen. This diagnosis is strongly suggested when calcified testicular masses are identified in the pediatric age group. round. lobulated.71 Sertoli cell tumour of the testis. well developed or abortive tubules are usually also present.70 Sertoli cell tumour. Necrosis is typically not evident. Tumours in patients with PeutzJeghers syndrome may be bilateral. varying in size from 1 cm to more than 20 cm in diameter.

but mitoses are rare. The youngest patient on record was 2 years old. 4. Most tumours on record are relatively small (0.2951}. In most cases the tumours are benign. 254 Tumours of the testis and paratesticular tissue .A Fig. Ultrastructure Charcot-Böttcher crystals. including precocious puberty and gynecomastia are found in a significant number of cases. but occur also as parts of the Carney and PeutzJeghers syndromes {1391}.4-1. but 20% are malignant.5 cm). Tumour cells have vesicular and relatively large nuclei and prominent nucleoli. whereas the remaining 40% are associated with genetic syndromes or have endocrine disorders {1391}. The stroma may be hyalinized. B Sertoli cell tumour mimicking seminoma. and may be discrete or anastomosing.73 A Sertoli cell tumour. In contrast to Sertoli cell tumours NOS. and typically shows broad areas of calcification. are rarely seen but are considered to be typical of Sertoli cells. and sclerosing Sertoli cell tumour. features of SSCT include small neoplastic tubules surrounded by dense sclerotic stroma. In 40% of cases the tumours are bilateral. most patients harbouring LCCST are young and the average age is 16 years.74 Sertoli cell tumour A Large cell calcifiying variant. Variants In addition to Sertoli cell tumours NOS two variants are recognized: large cell calcifying Sertoli cell tumour. Typically the tumours contain entrapped non neoplastic tubules. 4. The tubules may be solid or hollow. composed of filaments. Microscopic features of LCCST include nests and cords of relatively large polygonal cells with eosinophilic cytoplasm embedded in myxohyaline stroma. though a substantial proportion lack calcification. Cords and nests of cells in a fibrous stroma with focal ossification. B (LCCST) can be sporadic. Sporadic tumours account for 60% of cases. Large cell calcifying Sertoli cell tumour (LCCST) Large cell calcifying Sertoli cell tumour Sclerosing Sertoli cell tumour (SSCT) Sclerosing Sertoli cell tumour (SSCT) is rare and less than 20 cases of this variant are recorded {929. alpha-fetoprotein.2894}. human chorionic gonadotropin. Microscopically. often with abundant neutrophils. (30%) {2575. Endocrine symptoms. Only about 50 cases of this neoplasm have been reported so far. Tumour cells are invariably negative for placental alkaline phosphatase. They occur in adults and the average age at the time of diagnosis is 35 years. There are not enough data to determine whether the proposed variants such as "lipid rich variant" and "Sertoli cell tumour with heterologous sarcomatous component" {875} warrant separation from the Sertoli cell tumour NOS. B Large cell calcifiying Sertoli cell tumour. Differential diagnosis Sertoli cell tumours NOS need to be dis- A B Fig. Intratubular spread of the tumour cells is typically found in most cases {366}.

Endometrioid adenocarci- noma and metastases. and among the latter especially adenocarcinomas with pale or clear cytoplasm. Malignant Sertoli cell tumour ICD-O code 8640/3 Epidemiology Malignant Sertoli cell tumour not otherwise specified is rare {1194}. 4. which are usually not very prominent. B Fig. Age distribution does not differ from that of the benign form. 4. Lymphovascular invasion may be seen. Approximately one third has gynecomastia at presentation. Clinical features Some patients present with metastases. The most important differential diagnoses are classical and spermatocytic seminoma and variants of yolk sac tumour. are small. A Fig. They are PLAP and CEA negative. A Solid and tubular components. and necrosis may occur. Sex cord / gonadal stromal tumours 255 . usually more than 5 cm but range 2 to 18 cm. but apart from that no specific lesions or syndrome are known to be associated with malignant Sertoli cell tumour. the cellular features and Fig. Mitotic figures may be numerous.75 Sclerosing type of Sertoli cell tumour. sheet-like growth pattern is often prominent. as well as melanoma should also be considered. Two variants are distinguished: adult and juvenile types. Sertoli cell nodules. Lymphoplasmacytic infiltration is reported in some cases varying from sparse to pronounced and even with secondary germinal centres. The nuclei may be pleomorphic with one or more nucleoli. A fibrous. occurring from childhood to old age. most commonly to inguinal. incidentally discovered. and Leydig cell tumours. and they may be S100 positive. non neoplastic lesions composed of aggregates of small tubules lined by immature Sertoli cells and contain prominent basement membrane deposits. Histopathology Microscopically. The rete adenomas occur within the dilated lumens of the rete testis. 4.77 Malignant Sertoli cell tumour.76 Malignant Sertoli cell tumour. hyalinized or myxoid stroma occurs in varying amounts. Prognosis Most Sertoli cell tumours are benign. Immunohistochemical staining is helpful in defining the Sertoli cell nature of the tumour but not its malignant potential {1074.tinguished from Sertoli cell nodules. growth patterns are similar to those of the benign counterpart but tend to be more variable within the same tumour and between tumours. Granulosa cell tumour group Definition Granulosa cell tumours of the testis are morphologically similar to their ovarian counterparts. The solid. The macroscopic appearance may differ from that of the benign tumour by necrosis and haemorrhage. They stain for inhibin A. but is usually sparse.1194}. but usually not very intensely. Less than 50 cases have been reported. B Vimentin staining in the tubular component. The tumour cells are cytokeratin and vimentin positive and they may also be positive for epithelial membrane antigen. retroperitoneal and/or supraclavicular lymph nodes. Macroscopy They tend to be larger than the benign counterparts {2894}. and rete adenomas. however granulomatous reactions and intratubular germ cell neoplasia are not present in the surrounding testicular parenchyma. however.

1676 years). or have smooth muscle or osteoid {46}.79 Juvenile granulosa cell tumour. Note prominent cysts. as occurs in similar ovarian tumours {1433}. Granulosa-like cells are 256 Tumours of the testis and paratesticular . Most of the tumours are observed in the perinatal period. Necrosis or haemorrhage are unusual.2576.477. Tumour cells are round to ovoid with grooved nuclei (coffee-bean nuclei) with one to two large peripheral nucleoli. The microfollicular pattern is the most frequent. depending on the degree of cystic dilation. The tumour surface may show cysts from 1-3 mm in diameter. The tumour may intermingle with seminiferous tubules and infiltrate the tunica albuginea. 4. In all cases with ambiguous genitalia the karyotype is abnormal: 45X / 46XY mosaicism or structural anomalies of Y chromosome.1443. sometimes encapsulated. inhibin. gyriform. Neither gynecomastia nor endocrine disorders appeared associated. adult type. with solid areas and partially encapsulated. have a firm consistency and vary from yellow to beige. The tumour size varies from 0. grows slowly and only two dozen cases have been reported {1901}. External genitalia are ambiguous in 20% and the most frequent associated anomaly is mixed gonadal dysgenesis. Juvenile type granulosa cell tumour This tumour is multicystic and its structure resembles that of Graafian follicles. MIC2 (013-Ewing sarcoma marker). They vary from microscopic to 13 cm in diameter. preferentially located in the left testis {1896}. The average age at presentation is 44 years (range.1647}. Microfollicles consist of palisading cells. It involves an abdominal testis in about 30% of cases.1 812. even several years after the presentation {1223.8 to 5 cm in size {1453}. 2528}.2092. Prognosis The tumour metastasizes in 20% or more of patients. solid and pseudosarcomatous. Haemorrhage secondary to a torsion or trauma may make diagnosis difficult {407}. Fig. Tumour cells are immunoreactive for vimentin. and Müllerian-inhibiting hormone. Neither recurrences nor metastases have been observed {400. Macroscopy These tumours are circumscribed. insular. Some are incidental. Macroscopy These tumours are usually cystic. microfollicular. 4. Histopathology Several patterns occur: macrofollicular.6% of all prepubertal testicular tumours {1275}. followed by hypospadias.78 Granulosa cell tumour. The inner cells are similar to granulosa cells. Patients have elevated serum levels of both inhibin. trabecular. Cellular pleomorphism and mitotic figures are infrequent.1705. Although it is rare. Fig.2136. Some show focal theca cell differentiation. smooth muscle actin. comprising 6.2895}. as occurs in other sex cord-stromal tumours {1781}. and focally cytokeratins. The contralateral testis is often undescended too. except for those areas showing fusiform cell pattern. while the outer cells resemble theca cells. it is the most frequent congenital testicular neoplasm {1022. Clinical features The tumour presents as a scrotal or abdominal asymptomatic mass. Histopathology Cysts are lined by several cell layers.ICD-O codes Granulosa cell tumour Adult type granulosa cell tumour Juvenile type granulosa cell tumour 8620/1 8620/1 8622/1 Adult type granulosa cell tumour Incidence and clinical features This tumour is rare {1. and presentation after the first year of life is exceptional.2567}. which surround an eosinophilic material (Call-Exner bodies). About 25% of patients have gynecomastia.

and solitary fibrous tumour {601}. or less commonly. ICD-O code 8591/1 Tumours of the thecoma / fibroma group Definition Tumours of the thecoma/fibroma group resemble their ovarian counterparts. 8600/0 8810/0 Sex cord / gonadal stromal tumours. With the exception of one large and poorly characterized tumour {1811}. Mitoses are usually scant. with only about 25 cases reported. Theca-like cells are elongated and show scanty cytoplasm and few mitoses. These include tumours also recognizable as sex cord/gonadal stromal tumours but without specifically differentiated cell types. Call-Exner bodies are seen.2798}. long straight spindle cells with abundant cytoplasm. regularly outlined. and fibroma of gonadal stromal origin {1241}.2860}. Sex cord / gonadal stromal tumours: incompletely differentiated Definition Tumours composed largely of undifferentiated tissue in which abortive tubule formation. Neither recurrences nor metastases have been observed. vacuolated cytoplasm. Clinical features These tumours are rare. Positive immunoreaction. S-100 protein and cytokeratin have been observed. It is not associated with hormonal alterations. and is yellow-white to white. Although heterogeneous. perinuclear vacuoles and blunt ended nuclei. and scanty. and focal immunostaining to anti-Müllerian hormone {2180}. and focal dense bodies. incompletely differentiated gonadal stromal tumour {1809}. testicular fibroma {1902}.80 Sex cord stromal tumour of the testis. to both vimentin. sometimes painful mass usually in the third and forth decades. and focally to desmin. smooth muscle actin. granulosa cell tumours and Sertoli cell tumours. Occasionally. and S-100 protein. In some cases. numerous thin filaments. measuring 0. benign gonadal stromal tumour spindle fibroblastic type {64}. and granulosa. these tumours and most testicular granulosa cell tumours are keratin negative. euchromatic nuclei with inconspicuous nucleoli. Neither Sertoli cells nor granulosa cells are observed. Taken together these findings suggest granulosa cell differentiation in many of these incompletely differentiated tumours. Macroscopy The tumour is a firm. in slightly collagenized connective tissue with numerous small blood vessels.2661}.8 to 7 cm in diameter. islands of Leydig cells. well circumscribed. Theca-like cells immunoreact diffusely to vimentin. Sertoli. Leydig. Fibroma of gonadal stromal origin is a benign tumour. although up to four mitoses per high power field have been reported. thecoma-like Sertoli cell tumour {482}. Sex cord / gonadal stromal tumours 257 . Cell density and amounts of collagen vary. stromal tumour resembling fibroma {2547}. Ultrastructural examination reveals a dual epithelial smooth muscle cell differentiation {2048} and a similarity between the tumoural cells and both primitive Sertoli cells and preovulatory ovarian granulosa cells {2082}.g. smooth muscle actin. cytokeratins {956} and S-100 protein {2576}.1651. the tumour is seen within adjacent tubules {1905}. and this can be addressed by immunostains {65. theca cell tumour {2320}. Granulosa-like cells show diffuse immunostaining to vimentin. rarely encapsulated nodule. and are most often comprised of either short. The differential diagnosis includes leiomyoma. or evidence of other specific sex cord/gonadal stromal cell types are identified. Ultrastructural studies show desmosomes. Some malignant tumours such as primary testicular fibrosarcoma {2683} and stromal tumours should also be considered. Most intratesticular “thecomas” that have been reported are actually fibromas of gonadal stromal origin. Synonyms Diffuse stromal form of gonadal stromal tumour {2592}. the limited clinical followup available to date has been benign {932. the cystic fluid is mucinous. mixed forms Definition The mixed form may contain any combination of cell types e. The tumour presents as a slow growing.837. Seminiferous tubules {571} with germ cells {2671} may be entrapped. including Leydig cell tumours. Although most ovarian granulosa cell tumours are keratin positive.round and have spherical. and occasionally. to desmin. Inhibin and CD99 are non reactive. neurofibroma. myoid gonadal stromal tumour with epithelial differentiation {1904. although they are joined by desmosomes like Sertoli cells and granulosa cells {1726}. these tumours are most often reactive for both smooth muscle actin. which displays fusiform cells and variable degrees of collagenization. a pattern also seen in both adult and juvenile granulosa cell tumours. The differential diagnosis is yolk sac tumour. wavy to round.2170. Immunohistochemically. Histopathology Fusiform cells are arranged into fascicles or a storiform pattern. testicular stromal tumour with myofilaments {932}. 4. Tumour cells have ultrastructural features of both fibroblasts and myofibroblasts. many of these tumours are similar {2170}. Fig. ICD-O codes Thecoma Fibroma Histopathology Incompletely differentiated sex cord/gonadal stromal tumours are a heterogeneous group of testicular tumours that have been described under a variety of names but are not classifiable into more specific sex cord tumour types. spindle cells with nuclear grooves and a minor epithelioid component. Occasionally. unclassified sex cord-stromal tumour with a predominance of spindle cells {2170}. Reticulin envelops aggregates of cells but not individual cells. without haemorrhage or necrosis.

2591.814. B Stromal tumour. Some tumours are lobulated. They are poorly delineated. Leydig and granulosa cell tumours. Gynecomastia may be present {827. numerous mitoses including abnormal forms and vascular invasion {652.81 A. 4. B Fig.2592}.1812. Macroscopically they often show necrosis and haemorrhage.2053.2906}.2664} Testicular swelling of several months or years is the most common symptom. These tumours are usually very large. and cytokeratins {932. The mixed forms show the histologic features of the individual well differentiated components. The Sertoli-Leydig cell tumour. smooth muscle actin. A Malignant sex cord / gonadal stromal tumours ICD-O code 8590/3 About 18-20% of gonadal stromal tumours are malignant {1454}.ICD-O code 8592/1 Clinical features The tumours occur at all ages {1800. The differentiated areas react with appropriate antibodies for substances found in Sertoli. NOS 258 Tumours of the testis and paratesticular tissue . nuclear anaplasia.2664}. desmin. common in the ovary. The undifferentiated component may be positive for S-100 protein. Histologically. The cut surface shows generally well circumscribed white or yellow masses. 1800.875. they show cellular pleomorphism. 1726}. is rare in the testis {741. The tumours vary in size but may be large and replace the testis. 1812.

Tumours containing both germ cell and sex cord / gonadal stromal elements T. A Characteristic nested arrangement. testis specific protein Y-encoded (TSPY) {1448}.2566}. Most commonly. A B C Fig. About 50% of all patients with gonado- Immunoprofile The germ cells in gonadoblastoma express the VASA protein {2929}. Genetics Germs cells in gonadoblastoma have been reported to be aneuploid {1248}. involving the hyaline bodies or extensive. 25% of patients with mixed gonadal dysgenesis and Y component have gonadoblastoma and germ cell tumour {1620}. The stromal cells express inhibin and the Wilms tumour gene (WT-1) {1149}. In the second growth pattern the Sertoli cells surround large germ cells or in the third pattern the germ cells occupy the center of the nests and the Sertoli cells form a peripheral ring. In these tumours the germ cells are seen within tubules or form cohesive nests. Germ cell-sex cord/stromal tumours occur rarely in otherwise normal males {266.82 Gonadoblastoma. Gonadoblastomas contain evidence of Ychromosome material by fluorescence in situ hybridization {1163}. Differential diagnosis Sertoli cell nodules containing germ cells may be mistaken for gonadoblastoma. Tumours containing both germ cell and sex cord / gonadal stromal tumours 259 . Rarely. but in 8%.1390. B Gonadoblastoma with seminoma.2650}. In one series about 24% of patients with Turner syndrome had Y chromosome material {2026} and in another series 12. By the age of 40.X karyotype and Y chromosome material {1389. elements resembling Leydig or lutein-like cells may also be present. Macroscopy The gonads contain yellowish to tan nodules with a gritty cut surface.2350}. The estimated risk of developing gonadoblastoma in this setting is 15-25% {2026}. and overexpress p53 protein {1149}. Histopathology The lesion consists of immature Sertoli cells and germ cells which form rounded or irregularly outlined discrete aggregates. The tumours may consist of microscopic foci or can measure up to 8 cm {2350}. some of which are calcified. ICD-O code 9073/1 blastoma irrespective of the underlying abnormality develop germ cell tumours mainly seminomas. They also have features of intratubular malignant germ cells expressing PLAP and c-kit {1248}. Interestingly. C This nest has cylinders of basement membrane.2350}. 4. Mostly in the post pubertal patient.M. the stroma may contain large polygonal cells indistinguishable from Leydig cells. the Sertoli cells encircle rounded hyaline nodules and are intimately associated with basement membranes surrounding the nests.2266. other germ cell tumour types. Calcifications may be focal. The Y-chromosome contains the candidate gene of the gonadoblastoma locus {2286. gonadoblastoma is found in genotypical and phenotypical males {413. Ulbright Gonadoblastoma Definition A tumour composed of two principal cell types: large germ cells similar to those of seminoma and small cells resembling immature Sertoli and granulosa cells. In the latter only 7-10% of patients had gonadoblastoma.2% {930}. the seminomas and nonseminomas originating in dysgenetic Incidence and clinical features Gonadoblastoma is most commonly seen in mixed gonadal dysgenesis associated with ambiguous genitalia and 45.

This viewpoint. of the purported examples represent sex cord-stromal tumours with entrapped. grey or tan circumscribed masses. 260 Tumours of the testis and paratesticular tissue . gonads are most often diploid unlike those from non dysgenetic testis {351. Malignant behaviour has not been reported. thereby providing support that most. On microscopic examination. unclassified. unclassified Germ cell-sex cord/gonadal stromal tumour. non neoplastic germ cells. Recent evidence {2671}. which is often arranged in tubules or cords with transition to spin- dled stromal cells. but the sex cord-stromal component should be analysed for features that are associated with metastases in sex cordstromal tumours. 2142. and perhaps all. A Loose clusters of germ cells occur in a tumour consisting of small nests and cords of sex cord cells and spindled stromal cells. the predominant element is the sex cord-stromal component.2198}. as opposed to the nested pattern of gonadoblastoma {266. uniform nuclei having fine chromatin. while the sexcord-stromal elements have often been positive for alpha subunit of inhibin. These tumours have occurred mostly in young men who presented with masses.2563}. is controversial. B The germ cells have round nuclei with fine chromatin and inconspicuous nucleoli. They are commonly loosely clustered with clear cytoplasm and round.A B Fig. Immunostains for placental alkaline phosphatase and c-kit have been negative {2671}. however. 4. unclassified type is defined as a neoplasm having a combination of neoplastic germ cells and neoplastic sex cord-stromal elements arranged in a diffuse pattern. casts doubt on the neoplastic nature of the germ cells. The tumours are usually white.83 Germ cell-sex cord/gonadal stromal tumour. however. The germ cells are most common at the periphery but may be more diffuse or central.1648.1004. although an occasional case has been in a child. Germ cell-sex cord/gonadal stromal tumour.

Clinical features The patients ages range from 14-68 years.766. Symptoms of testicular swelling range from a few months to 20 years {214. Neuroendocrine granules can be identified by electron microscopy {2569. Macroscopy The macroscopic appearance varies Differential diagnosis The differential diagnosis includes carcinoma of the rete and mesothelioma. and only rarely with carcinoid syndrome {1045}. Carcinoids in teratomas have been included in the category of teratoma with somatic type malignancy {1805}. or pseudoglandulae.84 A Mucinous borderline tumour of the paratesticular tissue. They may be located in the tunica and paratesticular tissue as well as the testis. They are solid. Sesterhenn J. 2902}. chromogranin) {1970.2767. Calcifications may be present. Rarely. if mucin is present.1285. well differentiated endometrioid adenocarcinoma with squamous differentiation {2902}. . and yellow to dark tan.2923}. In the series by Berdjis & Mostofi it accounts for 0. Incidence These are very rare tumours.K.1906}. with the tumour type.R. Clinical features The ages range from 10-83 years. trabeculae.2902}.5 cm with a mean of 4. Histopathology The histologic appearance is identical to their ovarian counterparts.2923}. primary carcinoids of the testis are malignant metastasizing to lymph nodes. mucinous cystadenoma. Tumours of ovarian epithelial types Definition Tumours of testis and adjacent tissues that resemble surface epithelial tumours of the ovary. A B Miscellaneous tumours of the testis 261 Fig.23% {214}. They also include serous carcinomas {1242}. skin and skeletal system {1127.1938.g. Srigley H. The larger tumours may show necrosis. Histopathology The microscopic appearance is identical to that described in other sites but the trabecular and insular pattern predomi- nate. 4. Mostofi I.Miscellaneous tumours of the testis F.2923. ICD-O code 8240/3 Epidemiology The incidence is less than 1% of testicular neoplasms. Levin Carcinoid tumour Definition An epithelial tumour of usually monomorphous endocrine cells showing mild or no atypia and growing in the form of solid nests. Immunohistochemistry will be helpful to distinguish mesothelioma from papillary serous tumours.2166.2569.2932}. The cells are positive for endocrine markers (e.2393.g. The patients present with scrotal enlargement {2664}. The reader is referred to the volume dealing with ovarian tumours. Primary carcinoid of the testis usually presents as a mass. B Endometrioid carcinoma.A. Most of the lesions reported in the literature are serous tumours of borderline malignancy {570. and mucinous borderline tumours and cystadenocarcinoma {685. The rete carcinoma should be centered around or in the rete.0 cm to 9. ileum) can metastasize to the testis {1823}. The more solid tend to be carcinomas {2664. liver. Macroscopy The tumours measure between 1. mucinous cystadenoma {1295}. with a mean age of 46. Cystic lesions are usually serous tumours of borderline malignancy or. Carcinoids from other sites (e.2533}.6 cm.S. The differential diagnosis of mucinous carcinoma and endometrioid carcinoma should include metastatic adenocarcinoma.

7) years. 4. They vary in size from 1. The histology is similar to that of ovarian Brenner tumour with cysts lined by bland transitional Paraganglioma Nephroblastoma ICD-O code ICD-O code 8960/3 In the spermatic cord. Fig.5 to 10 cm and are functionally inactive. Inguinal and scrotal nephroblastomas have occurred in males 3. Macroscopically. these are rare.86 Brenner tumour of the testis. 8680/1 Nephroblastoma of testicular adnexa is identical to renal nephroblastoma and is a triphasic tumour comprised of metanephric blastema. 262 Tumours of the testis and paratesticular tissue .2452} and 2 unreported cases are in the Genitourinary Tumour Registry of the Armed Forces Institute of Pathology. Most examples of Brenner tumour are benign. the solid and cystic masses vary from less than1 to 5 cm in diameter. 4. B epithelium. solid nests of transitional type epithelium and a cellular spindle cell stroma. Nephroblastomas may occur as a paratesticular tumour {1976} or as a metastasis from a renal nephroblastoma {2303}.729. and mesenchymal structures. Brenner tumour ICD-O code 9000/0 Tumours histologically identical to Brenner tumour of ovary may be encountered in the testis and paratesticular region {312} The age range is 37-70 (mean 57. although one malignant example showing local invasion. Histologically. B Brenner tumour of the testis. epithelial structures consisting of tubular and/or glomerular structures. One mixed Brenner and adenomatoid tumour has been reported {1911}.5 years of age and younger {116}.A Fig. they are indistinguishable from those in other sites. lymphatic space involvement and metastatic deposits in para-aortic lymph nodes has been described {357}. Primary nephroblastoma has been staged and treated according to NWTS protocol. Paratesticular tumours have been associated with heterotopic renal anlage and one paratesticular nephroblastoma metastasized to the lung {1976}.698.85 A. Five cases have been reported in the literature {605.

Sonographically lymphomatous masses will generally be hypoechoic. “B-symptoms” are rare in primary lesions. Primary testicular plasmacytoma is less frequent than DLCL {98. 1429. which may completely infiltrate the testis {913. grey and necrotic or haemorrhagic single or multiple nodules or diffuse enlargement of testis or paratesticular tissues {767. have been reported {1166. and in this age group TL is the single most frequent testicular tumour {2001. Secondary involvement of the testis occurs in about 5% of childhood systemic lymphomas {547. They are generally discrete hypoechoic lesions. Incidence and clinical features Testicular lymphoma (TL) and plasmacytoma The majority of primary lymphomas of the male genital tract arise in the testes {756. Macroscopically.2076}. Bilateral simultaneous involvement of the testis is typical for lymphoblastic lymphoma. 4.2718} and plasmacytomas {758} are rare as well.2944.2945}. Lymphoma and plasmacytoma of the testis and paratesticular tissues 263 .2945}.Lymphoma and plasmacytoma of the testis and paratesticular tissues A.1761. Clinical features and macroscopy Primary lymphoma and plasmacytoma of testis and paratesticular tissues typically present with unilateral enlargement of the scrotum or swelling in the inguinal region.643. Primary (stage IE) TL constitute 4060% of all TL {1429. In contrast to most germ cell tumours. Most patients with TL are 60-80 years of age (19-91). Although less common. 1999. EBV-associated T/NK-cell lymphomas of nasal type {402} are exceptional.2945}. Paratesticular lymphoma Paratesticular lymphoma may appear radiologically as multiple nodules or as diffuse infiltration of the epididymis or spermatic cord {2070}. and 2560% of TL show extension to paratesticular sites {509. primary diffuse large Bcell lymphoma (DLCL) is the single most frequent lymphoma (70-80%) {1429.2938.2944}. When multiple masses are identified involving both the testicular and extratesticular tissues lymphoma is the first consideration. 1288. The left spermatic cord is normal (small arrow). all in older men.2076. Secondary involvement of paratesticular structures in the absence of testicular lymphoma is exceedingly rare {1073}.J.1657}. 2% of all high grade lymphomas and 5% of all extranodal lymphomas in men. Primary MALT lymphomas {1174}. Primary paratesticular lymphoma appears to peak in a young (20–30 years of age) {1073} and an older (34–73 years of age) {1073. Woodward Definition Primary lymphomas or plasmacytomas of testes or paratesticular tissues arise in the testicles. follicular lymphomas {756}. Only single cases of primary plasmacytoma of the testis.756.2945}. Testicular lymphomas (TL) constitute 2% of all testicular neoplasms. epididymis or spermatic cord and are neither associated with lymphoma elsewhere nor leukemia. Bilateral paratesticular lymphoma is rare as well {1670}.2541}.2945}.1968. Paratesticular lymphoma and plasmacytoma The majority of paratesticular lymphomas is seen in connection with TL.2825}. DLCL cells infiltrate around seminiferous tubules. Involvement of these anatomic structures by systemic lymphomas/leukemias or plasma cell myeloma defines secondary testicular or paratesticular lymphomas or plasma cell neoplasias. 1296.767.1670. 2497}. B Lymphoma involving the spermatic cord. Axial CT image through the level of the spermatic cord shows diffuse enlargement on the right side by a soft tissue mass (large arrow). involvement of the contralateral testis during lymphoma recurrence is common (10-40%) {1429.2944. Primary paratesticular lymphomas {1073. but rare in other entities {756}. One case was associated with HIV infection {2138}. It forms nodules composed of A B Fig. 2944. and CD56+. interstitial fibrosis. Imaging Testicular lymphoma The sonographic appearance of testicular lymphoma is variable and often indistinguishable from that of germ cell tumours. In children primary testicular lymphomas are rare and typically occur prior to puberty (3–10 years of age) {767. The testes are usually also involved. lymphoma is often bilateral and multifocal.2825}. Histopathology Testicular lymphoma (TL) and plasmacytoma In adult testis.756.1486.1073.2944.2718}. It may also involve the extratesticular tissues. tubular hyalinization and loss of tubules {756. metastases can give a similar appearance. A Coronal T2-weighted MRI shows these lesions as hypointense masses (arrows) within the normal higher signal parenchyma. 2718} age group with a favourable clinical course only in the former {1073}. Marx P. By contrast.1670. cause arrest of spermatogenesis. T-cell lymphomas {1131.1296}. the cut surface usually reveals poorly demarcated tan.87 Lymphoma.

including the contralateral testis (1040%) and central nervous system (CNS) parenchyma (20-27%) {1429. cell lymphomas {1073. Primary pediatric follicular lymphomas of testis have an excellent prognosis in spite of grade III morphology: after a follow-up of 18 – 44 months there was no death after orchiectomy and chemotherapy {767.2718. the prognosis of primary lymphomas of the epididymis.1922.2945}. B Myeloid leukaemia (chloroma). the majority of testicular lymphomas represent secondary involvement by Burkitt. secondary testicular involvement in systemic B-cell lymphomas does not confer a poor prognosis. Prognostically favourable factors in TL and spermatic cord lymphomas are lymphoma sclerosis {756}. Primary follicular lymphoma of the testis in prepubertal children appears to be a distinct entity due to typical morphological features of grade III follicular lymphoma (+/. bilateral. 1761.2945}. However.2370.1999.2076}. Somatic genetics and genetic susceptibility Specific genetic aberrations have not been published. 264 Tumours of the testis and paratesticular tissue . In children.1166}.1288. 1701}. allowing for gonadal function to be preserved {547}. anthracyclin use {2370. The primary (stage IE) lymphomas of the testis and spermatic cord have the worst prognosis among all extranodal lymphomas. In older patients.18) translocation. while invasion of seminiferous tubules is rare {758}. early stage. in testicular pediatric primary follicular lymphoma absence of bcl-2 expression.1670.2944. 2076}. variable expression of CD10 and usually strong bcl-6 positivity are characteristic {767. 2718}.2076}.2738}.2718}.88 A Lymphoma.2718} and a single EBV-associated intravascular large cell lymphoma of T-lineage {137} were seen. Pediatric primary follicular lymphoma of the testis combines a Fig. DLCL or lymphoblastic lymphoma {547. Primary testicular and paratesticular plasmacytoma has a favourable prognosis {758.2945}. is much better {2718}.and 10-year overall survival rates were 37-48% and 19-27%. combined modality treatment {1429.89 Lymphoma with interstitial growth surrounding a seminiferous tubule. particularly in patients <30 years. diffuse large B- Immunohistochemistry There are no immunohistochemical peculiarities in testicular and paratesticular lymphomas or plasmacytomas.1761. Paratesticular lymphomas and plasmacytoma Among lymphomas confined to the epididymis. The 5.1568. A B Fig. follicular lymphomas (grade II and III) and a low grade MALT lymphoma have been described in patients 20-30 years of age {1073. while prognosis is poor in the context of plasma cell myeloma {758. CNS involvement occurs in 15-20% of stage IE TL and spermatic cord lymphomas {1429.2076} and a good prognosis. Surprisingly.1761.2944. that exhibit intertubular growth.typical grade III follicular morphology with combined absence of t(14. of which 71-91% involve extranodal sites.1296}. respectively {1429. Plasmacytoma in the paratesticular tissue is almost always associated with testicular plasmacytoma and plasma cell myeloma {1073} though exceptions occur {758}.1999. closely packed atypical plasma cells. the median survival was 32-53 months {1429.2945} and. and these children can usually be cured by chemotherapy alone. with 5 year overall survival rates of 70-79% {1429. Prognosis and predictive factors In aduts the prognosis of testicular lymphoma is generally poor: taking all stages and histological lymphoma subtypes into account. Relapses in TL occur in >50% of cases. BCL-2 rearrangement and p53 abnormalities {1999. In children.2944}. 4. in some studies. young age.diffuse large cell areas) but peculiar immunohistochemical and genetic properties {767. 4. By contrast.

Tumours of collecting ducts and rete

L. Nochomovitz

Adenoma
Definition A benign tumour of rete epithelial origin that occurs within the dilated rete and typically has a tubular pattern resembling Sertoli cell tumour. ICD-O code 8140/0

Clinical features and histopathology This is a rare tumour that mostly occurs in adults. It typically forms polypoid nodules composed of tubules that project into the dilated lumen of the rete testis. The tubules resemble those seen in benign Sertoli cell tumours.

Fig. 4.90 Adenoma of the rete testis. Note the cysts.

Fig. 4.91 Rete testis carcinoma.

Adenocarcinoma
Definition Recommended criteria for the diagnosis of adenocarcinoma of the rete testis are: no histologically similar extrascrotal primary, tumour centred on testicular hilum, absence of conventional germinal or non germinal testicular cancer, histologic transition from unaffected rete testis, solid growth pattern {1908}. ICD-O code 8140/3

Epidemiology and clinical features Rete testis carcinoma is rare, its etiology unknown. The tumour, predominating in the fourth through eighth decades, is usually associated with a scrotal mass, tenderness, or lumbar pain. It may be masked by an inguinal hernia, hydrocele, fistula, sinus or epididymitis. Symptoms are brief or extend over years. Locally recurrent tumour nodules and abscesses may involve the scrotal and perineal skin. A statistical analysis, based on published data, was reported {2288}. Macroscopy The carcinoma usually forms a non encapsulated firm, pale rubbery hilar mass. A cystic component, if any, is usually minor. Reported lesional size ranges from 1.0-10.0cm. The boundary between

A

B
Fig. 4.92 A Sertoliform cystadenoma of the rete testis. B Adenoma of the rete testis. Note the cystic dilatations.

Tumours of collecting ducts and rete 265

testicular parenchyma and tumour tends to be blurred where the tumour infiltrates the testicular interstitium. Nodular excrescences may stud the tunics and the spermatic cord. Histopathology The low power image of rete testis adenocarcinoma comprises large cellular tumour nodules with interspersed, smaller cellular clumps. Slit-like ramifications, reminiscent of Kaposi sarcoma, may per-

meate these cellular aggregates. The solid cellular zones may show sharply defined necrotic foci. Typically, neoplastic protuberances bulge into the residual dilated rete testis, the channels of which appear dilated. Actual and convincing transition from tumour to normal rete epithelium is the strongest evidence for the diagnosis, but may be difficult to demonstrate. Cellular papillary formations may project into open spaces, but frankly cystic lesions that resemble

serous tumours analogous to those of the ovary and peritoneum should not be classified as rete testis carcinoma. Of the tumour types in the differential diagnosis, mesothelioma in particular must be carefully excluded {164,2429}. The tumour may extend to the epididymis, spreading to the para-aortic, iliac and other lymph nodes, to various viscera, and to bone. In one analysis, 56% of 22 patients succumbed within the follow-up period.

A

B

C

D

E

F

Fig. 4.93 Carcinoma of the rete testis. A Tumour nodules between distended spaces of rete testis. B Tumour aggregates elicit desmoplastic response among dilated rete testis spaces. C Tumour cell nodules next to dilated vessels. D Solid tumour area with brisk mitotic activity. E Tumour infiltrates between atrophic, hyalinised seminiferous tubules. F Tumour cells encircling an atrophic seminiferous tubule.

266 Tumours of the testis and paratesticular tissue

Tumours of paratesticular structures

C.J. Davis P.J. Woodward L.P. Dehner M.A. Jones J.R. Srigley

I.A. Sesterhenn W.L. Gerald M. Miettinen J.F. Fetsch

Adenomatoid tumour
Definition A benign tumour of mesothelial cells characterized by numerous gland-like spaces, tubules or cords. Synonym Benign mesothelioma. ICD-O code 9054/0

the third through the fifth decades (mean age 36 years) {1800}. They present as small, solid intrascrotal tumours, and are usually asymptomatic. They have typically been present for several years without appreciable growth and are uniformly benign {1800,2664}.

where they can grow intratesticularly. The latter presentation is indistinguishable from testicular germ cell neoplasms. Localization Most of these occur in or near the lower pole or upper pole of the epididymis but other sites include the body of the epididymis, the tunica vaginalis, tunica albuginea and rete testis. Rarely the parietal tunica or spermatic cord may be involved {1800}. Macroscopy and histopathology These are usually small tumours, 2.0 cm or less, but they have ranged from 0.4 to 5.0 cm {2051}. They are round or oval and well circumscribed although they can also be flattened and plaque-like. Microscopically these consist of eosinophilic mesothelial cells forming solid cords as well as dilated tubules with flattened lining cells which may initially suggest an endothelial appearance {166}. Vacuolated cytoplasm is a prominent feature of the cells. The stroma is usually fibrous but may consist largely of smooth muscle. Ultrastructural and immunohistochemical features of these tumours support their mesothelial cell origin. There is an absence of epithelial/carcinoma markers MOC-31, Ber-Ep4, CEA, B72.3, LEA 135 and Leu M1 and also factor VIII and CD34. They invariably express cytokeratin AE1/AE3 and EMA {586,589}.

Incidence Adenomatoid tumours are the most common tumours of the testicular adnexa, representing 32% of all tumours in this location {287,1800} and 60% of all benign neoplasms in this area {2664}. Clinical features Signs and symptoms These begin to appear in the late teens and up to 79 years and most are seen in

Imaging Adenomatoid tumours are smooth, round, and well circumscribed masses of variable size generally arising in the epididymis. They are typically described as hyperechoic and homogeneous. This should not, however, be considered characteristic as great variability has been reported {801,1475}. The most important point is to clearly identify the mass as extratesticular and if it can be shown to be arising from the epididymis, adenomatoid tumour is the most likely diagnosis. They may also arise from the spermatic cord and tunica albuginea,

A

B

Fig. 4.94 Adenomatoid tumour. A Longitudinal ultrasound image shows a well defined, slightly hypoechoic, extratesticular mass in the region of the epididymal tail (cursors). (T - testis). B Coronal, gadolinium enhanced, T1-weighted MR image of scrotum shows an enhancing mass in the left epididymal head (black arrow). The epididymis on the right is normal (white arrow). (T - testes).

Malignant mesothelioma
Definition Malignant tumours originating from the tunica vaginalis or tunica albuginea. ICD-O code 9050/3

A

B

Fig. 4.95 Adenomatoid tumour. A Adenomatoid tumour protruding into the testis. B Paratesticular adenomatoid tumour.

Incidence Intrascrotal mesotheliomas are invariably described as rare although they are the most common paratesticular malignancies after the soft tissue sarcomas {287,1239,2051}. As of the year 2002 Tumours of paratesticular structures 267

A

B

the surgical scar and adjacent tissue of the skin, scrotum, epididymis or cord and metastasis have been found in inguinal and retroperitoneal nodes, abdominal peritoneum, lungs, mediastinum, bone and brain {1239,2051}. There have been reports of peritoneal mesotheliomas presenting initially in the tunica vaginalis {36} and of simultaneous mesotheliomas of pleura, peritoneum and tunica vaginalis {124}. We have seen other cases in which the intrascrotal lesions preceded peritoneal and/or pleural disease by up to four years. Histopathology Microscopically about 75% of these will be purely epithelial in type while the others are biphasic, with varying amounts of the sarcomatoid morphology {287,1239, 2051}. The epithelial type usually shows a papillary and tubulopapillary morphology, often with solid sheets of cells. The cell structure is variable; the cells covering the papillations are usually rounded or cuboidal, often with a bland appearance but may be flattened or low columnar. Where the cells are arranged in solid sheets, variation in size and shape is the rule. The cytoplasm is eosinophilic and varies in amount {1800}. Nucleoli are often prominent. The sarcomatoid element shows fascicles of spindle cells which may include a storiform pattern similar to malignant fibrous histiocytoma {1239}. Mesotheliomas of the tunica will usually show cellular atypia of the mesothelial surface indicative of in situ neoplasia {2051}.

C

D

Fig. 4.96 A Adenomatoid tumour. This is the classic tubular morphology with vacuolated cells. B Vacuolated cells mimicking endothelial cells. Masson trichrome stain. C In this example the stroma is entirely smooth muscle. Masson trichrome stain. D Peripheral lymphocytic aggregates are commonly seen.

only 80 cases had been reported {353}. In one study of all mesotheliomas, including pleural, peritoneal and pericardial, only 6 of 1785 were of tunica vaginalis origin {1836}. Clinical features The age at presentation ranges from 6 to 91 years with most occurring between ages 55 and 75 {2051}. 10% of reported cases have been in patients younger than 25 years {2051,2664}. In descending order of frequency paratesticular mesotheliomas have been discovered incidental to hernia repair, a palpable tumour associated with a hydrocele and a palpable tumour only. There have also been sporadic cases presenting with localized soreness or swelling, acute hydrocele, recurrent hydrocele, haematocele and diffuse thickening of the spermatic cord. It is now possible to anticipate the correct diagnosis with imaging studies, particularly when combined with cytology {2051}. Demonstration of multiple nodular masses within a hydrocele, particularly if irregular contours are seen, will generally prove to be a mesothelioma {819}. The incidence of asbestos exposure in patients with tunica vaginalis mesotheliomas has been cited as 23% {2051}, 41% {1239} and even 50% in a small series {135}. To date, asbestos exposure is the only

known risk factor and the incidence of exposure correlates with that reported for pleural tumours {1239}. Macroscopy The common appearance of the gross specimen is thickening of the tunica vaginalis with multiple friable nodules or excrescences. The tunica albuginea may also be involved. The fluid of the hydrocele sac is described as clear or haemorrhagic {1239,1800,2051}. White or tan masses of firm tissue may be found where the tumour infiltrates into the hilus or periphery of the testis or into the epididymis or spermatic cord. Tumour spread Most recurrences occur in the first 2 years of follow-up {2090} and are seen in

Immunohistochemistry By immunohistochemistry the cells are uniformly reactive with cytokeratin (AE1/AE3) in both epithelial and spindle cell elements. EMA and vimentin are also usually positive and calretinin has been

Fig. 4.97 Malignant mesothelioma. Tunica vaginalis with multiple friable excrescences.

Fig. 4.98 Malignant mesothelioma with tubulopapillary morphology.

268 Tumours of the testis and paratesticular tissue

Epidemiology Nodular mesothelial hyperplasia (NMH) was first described in 1975 {2228}. Approximately one case of NMH occurs in 800 to 1000 hernia sacs that are examined microscopically. Approximately 70% of cases are diagnosed in patients 10 years of age or less, (median 1.5 years, range 6 weeks-84 years). There is a 3-10:1 male predilection, reflecting the predominance of inguinal hernias in male children {1519}. Etiology The presumptive etiology is a reaction of the hernia sac to a variety of injuries including incarceration and inflammation. Clinical features Clinical manifestations are those of a hernia. Histopathology One or more nodules, either attached or unattached to the mesothelial surface of the hernia sac are identified. Adjacent to the nodule, the surface mesothelium is hyperplastic with individual cuboidal cells and a population of submesothelial cells resembling those of the nodule. The unattached nodule is often accompanied by individual cells floating within the lumen of the hernia sac and pseudoglandular and papillary profiles of cells are present in some cases. The polygonal cells vary from innocuous to moderately pleomorphic. Mitotic activity is low. Fibrin and inflammatory cells are also present. The lesion lacks the overtly malignant features of a malignant mesothelioma, carcinoma or sarcoma. Multinucleated cells and especially strap-like cells in NMH have been confused with embryonal rhabdomyosarcoma in the past.

Fig. 4.99 Malignant mesothelioma. Exophytic tumour growth into the scrotal sac. Note in situ malignant change of mesothelial surface.

invariably positive {1239,2051}. CEA, B72.3, Leu M1 and Ber-Ep4 have been negative {2664}.

Ultrastructure Ultrastructural features are characteristic of mesothelial cells.

Benign mesothelioma
This designation has been given to the rare examples of cystic mesothelioma and to the well differentiated papillary mesothelioma (WDPM) both of which are similar to those occurring in the peritoneum. The cystic mesotheliomas present as scrotal swellings suggestive of hydrocele and consist of multiple cystic structures with no cellular atypia. Lymphangioma is almost invariably the lesion to be excluded and this should be readily accomplished with the epithelial and endothelial markers {1434,2051}.

The WDPMs present as one or more superficial nodules or granular deposits over the surface of the hydrocele sac {353,2051}. Microscopically there is a single row of flattened or cuboidal mesothelial cells lining fibrovascular papillae {348,353,2051,2852}. Cellular features are bland. Most of these occur in young men in the second and third decades and have behaved in a benign fashion although it is widely regarded as a borderline mesothelioma since some have proved to be aggressive {348,353, 1239}.

Nodular mesothelial hyperplasia
Definition A proliferative process typically discovered in a hernia sac as an incidental finding consisting of cohesive collections of polygonal cells forming one or more attached or unattached nodules.

A

B
Fig. 4.101 Nodule of proliferating mesothelial cells.

Fig. 4.100 Benign mesothelioma. A Well differentiated papillary mesothelioma. Note superficial nature of the tumours. B Well differentiated papillary mesothelioma. Note papillations with bland cuboidal cell lining.

Tumours of paratesticular structures 269

Immunoprofile Ordóñez and associates {1973} examined one case by immunohistochemistry and concluded that the so-called mesothelial cells are histiocytes, although the originally described lesions may not represent the same process {2769}. An analogous proliferation of the pleura has been encountered and reported as nodular histiocytic hyperplasia {401,455}.
Prognosis The lesion is benign.

Adenocarcinoma of the epididymis
Definition Adenocarcinoma of the epididymis is a rare gland forming, malignant neoplasm derived from epididymal epithelial cells. ICD-O code 8140/3

Fig. 4.102 Carcinoma of the epididymis.

Incidence and clinical features It occurs in men from 27-82 years, mean age, 67 years. Only 10 well documented cases have been reported {418,770,833, 1095,1240,1438,2814}. The clinical presentation is a palpable scrotal mass and/or testicular pain and frequently a hydrocele. Macroscopy and histopathology The tumours are centred in the epididymis and range from 1.0-7.0 cm. in greatest dimension with a tan or greywhite colouration. Foci of haemorrhage and necrosis may be present. Epididymal adenocarcinoma may have tubular, tubulopapillary, papillary or cystic growth patterns often in combination {1240}. Tumour cells are columnar or cuboidal and often contain clear cytoplasm due to glycogen. The immunohistochemical profile of these tumours includes strong reactivity for cytokeratins (AE1/3) and epithelial membrane antigen. Staining for CEA, Leu M1, prostate specific antigen, Leucocyte common antigen and S100 protein have been reported as negative {418,833,1240}. Electron microscopic features include desmosomal junctions, cilia, glycogen particles and multivesicular bodies {1240}. Prognosis Meaningful follow-up data exists in only 5 patients, three of whom developed

Fig. 4.103 Papillary cystadenoma of the epididymis. Ectatic duct with clear cell lining and colloid-like luminal fluid.

metastases {418,770,833,1240}. The tumour invades locally and metastatic spread is to the retroperitoneal lymph nodes and lungs.

Papillary cystadenoma of epididymis
Definition A benign papillary epithelial tumour in the epididymal ducts. ICD-O code 8450/0

Incidence These benign tumours are seen in about 17% of patients with von Hippel-Lindau disease {1431,2664} but, overall, they are generally regarded as rare or uncommon {206,877}.

Clinical feature These present as asymptomatic nodules in the region of the head of the epididymis. They have usually been present for a number of years and enlarged very little {1800}. Some have been discovered during evaluation for infertility, and this diagnosis should be considered when azoospermia is associated with an epididymal mass {2104}. They occur between 16 and 81 years (mean 36 years) although a few have been seen in females in the broad ligament and pelvic cavity {2384}. A few have also occurred in the spermatic cord {206}. The lesions have been bilateral in 30-40% of cases. In von Hippel-Lindau disease they are more frequently bilateral {287,2111}. Macroscopy Grossly, the tumours range from 1.6 to 6.0 cm and are solid or cystic and tan,

270 Tumours of the testis and paratesticular tissue

A
brown or yellow in colour. The cut surface may be multicystic. Histopathology Microscopically, two findings are common to all lesions: ectasia of the efferent ducts and papillary formations. The tumours seem to arise from the efferent ducts, which show all degrees of ectasia from slight dilatation to microcyst formation {1236}. The ducts are lined by cuboidal or columnar cells with clear or vacuolated cytoplasm and often are filled with a colloid-like secretion. Papillary processes, simple or complex, arise from the walls of the ducts and may completely fill the cysts. Rarely, there have been foci of a histological pattern similar to that of the cerebellar haemangioblastoma {1800}. By immunohistochemistry they react with epithelial markers (Cam 5.2, AE1/AE3 and EMA) {877,2630}.

B
Genetics The VHL gene has been identified and mapped to chromosome 3p25-26. Mutations in the VHL gene, leading to allele loss, have been detected in sporadic epididymal papillary cystadenoma {877} and also in those of patients with von Hippel-Lindau disease {206}. Epidemiology Melanotic neuroectodermal tumour is a rare neoplasm which typically involves facial and skull bones. It may arise in the epididymis where at least two dozen examples have been reported {1073}. Most cases affect infants under the age of one and the oldest report is in an 8 year old. Clinical features Patients present with a firm mass, sometimes associated with hydrocele. One patient had a mild elevation of alphafetoprotein and there is elevation in urinary vanillylmandelic acid/homovanillic acid levels in some cases {1073}. Macroscopy Macroscopically, melanotic neuroectodermal tumours are circumscribed, round to oval, firm epididymal masses that measure less than 4 cm in diameter. They

Fig. 4.104 Papillary cystadenoma of the epididymis. A Papillary tumour with clear cell morphology. B Papillary tumour fills the lumen of an ectatic epididymal duct.

Melanotic neuroectodermal tumour
Definition Melanin containing tumour with varying proportions of two cells types in a cellular fibrous stroma. ICD-O code 9363/0

Synonyms Retinal anlage tumour, melanotic hamartoma, melanotic progonoma.

A

B

Fig. 4.105 A Melanotic neuroectodermal tumour of infancy. Bland-like structures formed by melanin containing epithelioid cells. B Melanotic neuroectodermal tumour of infancy. SYN expression.

Tumours of paratesticular structures 271

2365}. 4. Immunoprofile Melanotic neuroectodermal tumour expresses a variety of epithelial. Fig. Ultrastructure Electron microscopy shows that the small neuroblastic cells have cytoplasmic processes with microtubules and occasional dense core granules. Clinical features The patients range in age from 5-37 A 272 Tumours of the testis and paratesticular tissue B Fig. or grooved with finely dispersed chromatin and one or two small nucleoli. either inguinal or retroperitoneal {566. The scant cytoplasm is light or eosinophilic and may contain glycogen. The nodules are intimately associated with the tunica. especially in the small cell component. Histopathology There is usually a dual population of cells.often have a grey-white cut surface and may show areas of dark pigmentation.108 Desmoplastic small round cell tumour. Cell borders are prominent. Larger melanin containing epithelioid cells form nests. glial fibrillary acidic protein and desmin may also be seen. The nuclei are round. S100. Macroscopy The tumours are firm and present as multiple varying sized nodules ranging from a few millimeters to 9.1235} No distant metastasis has been documented. The larger cells show evidence of both epithelial and melanocytic differentiation with desmosomal attachments and premelanosomes and mature melanosomes. Anti desmin staining. cords and glandlike structures. 4. Normal and abnormal mitoses are common. squamous metaplasia and glandular or tubular formations can be seen.5 cm. ICD-O code 8806/3 Sites of involvement The pelvic and abdominal cavities are mostly involved followed by the paratesticular region {528. synaptophysin.106 Desmoplastic small round cell tumour.1971. years. neuron specific enolase. Fig. melanocytic and neural markers {1273. 4. 2062}. A Note the small nests in dense stroma. Occasionally. They present with hydroceles or scrotal masses without hydroceles. Two examples have demonstrated lymph node metastasis. .107 Desmoplastic small round cell tumour. Desmoplastic small round cell tumour Definition A malignant serosa related small round cell tumour with an epithelial growth pattern in a desmoplastic stroma. Mitoses may be identified.857. Histopathology These consist of well delineated nests and anastomosing cords of rather uniform small cells supported by a prominent desmoplastic stroma. respectively {2062}. One case showed sparse intraand extra-cellular mucin production. B Higher magnification shows nests of small cells surrounded by desmoplastic stroma. Prognosis Melanotic neuroectodermal tumour of epididymis generally behaves in a benign fashion but may recur locally. Smaller neuroblast-like cells with high nuclear to cytoplasmic ratios are closely apposed to the larger cells. oval or elongated. Histogenesis The histogenesis of melanotic neuroectodermal tumour is unknown although it is thought to be a dysembryogenetic neoplasm which is nearly always congenital. The large cells typically stain for cytokeratins and HMB45. Single cell necrosis and comedo like necrosis are commonly present.

Interestingly. EMA and vimentin are also positive. Diagrammatic representation of chromosomal breakpoints in DSRCT with t(11. The most commonly identified EWS-WT1 chimeric transcript is composed of an in-frame fusion of the first seven exons of EWS.q12).2314} unique to this tumour. Immunoprofile The tumour shows dual differentiation with keratin and desmin expression. Prognosis Most patients develop peritoneal and retroperitoneal disease within 2 years and die within 3-4 years. but by microscopy it has to be separated from other small round cell tumours involving the paratesticular region. Other benign lesions include a variety of nerve sheath tumours (neurofibroma {1182}.1423}. The desmin reactivity shows a dot pattern.q12). Differential diagnosis Macroscopically.109 Desmoplastic small round cell tumour DSRCT. suggesting that the preservation of the last three zinc finger motifs of WT1 is crucial to the sarcomagenesis. Fig. Intranuclear chimeric protein can be detected and shown to contain the carboxy terminus of WT1 {856}.Fig. the most common primary site of DSRCT. They do not show the desmoplastic stroma and nested growth pattern. primarily those undergoing transition from mesenchyme to epithelium. {240. All chromosome 11 translocation breakpoints involve intron 7 of WT1. Detection of the EWS-WT1 gene fusion and chimeric transcript serves as a sensitive and specific marker for DSRCT and has proven useful in the differential diagnosis of undifferentiated small round cell tumours of childhood {856}. This stage of differentiation is reminiscent of DRCT with early features of epithelial differentiation.2139}. Male angiomyofibroblas- Tumours of paratesticular structures 273 . These include embryonal rhabdomyosarcoma and lymphoma. and testicular adnexa ICD-O codes Lipoma Leiomyoma Neurofibroma Granular cell tumour Male angiomyofibroblastomalike tumour (cellular angiofibroma) Calcifying fibrous (pseudo) tumour Fibrous hamartoma of infancy Liposarcoma Leiomyosarcoma Malignant fibrous histiocytoma Rhabdomyosarcoma 8850/0 8890/0 9540/0 9580/0 8826/0 8850/3 8890/3 8830/3 8900/3 Incidence Scrotal mesenchymal tumours are rare and their etiology is poorly understood. WT1. encoding the last three zinc-finger of the DNA binding domain. in a specific period of development {2113.2218. One patient with a solitary tumour involving the epididymis developed retroperitoneal disease 18 years post orchiectomy. Genetics DSRCT is characterized by a specific chromosomal abnormality. Immunohistochemistry will be helpful. About 91% of tumours express EWSWT1 gene fusion transcript {2334}. has a high transient fetal expression of WT1 gene. t(11. 4. and very infrequently introns 8 and 9. leiomyomas and lipomas. involving two chromosomal regions previously implicated in other malignant developmental tumours. many lesions designated as lipoma of the spermatic cord are reactive accumulations of fat related to hernial sac. on 22q12 and the Wilms' tumour gene.22) (p13. EWS. 4. the serosal lining of body cavities. lymphangiomas.110 Desmoplastic small round cell tumour DSRCT. schwannoma and granular cell tumour). and exons 8 through 10 of WT1. the tumour is similar to mesothelioma. Diagrammatic representation of chromosomal breakpoints in DSRCT with EWS-WT1 fusion transcript types. In our experience. encoding the potential transcription modulating domain. The four most frequently reported benign tumours are haemangiomas. Mesenchymal tumours of the scrotum. NSE. Rare variants including additional exons of EWS occur {102}. WT1 is expressed in tissues derived from the intermediate mesoderm. spermatic cord. The translocation results in the fusion of the Ewing sarcoma gene. The majority of chromosome 22 breakpoints involve the intron 7 of EWS.22)(p13.858. on 11p13 {564. Metastases involve liver and lungs.

the scrotal superficial. 4. these tumours tend to have a protracted course with common recurrences and dedifferentiation in a minority of cases. It is displacing both testes to the left (long arrows). occurrence below the age of 30 years is very rare. In our experience.1886}. Axial CT image shows a large righted sided scrotal mass.782. 4. 12) and have an excellent prognosis with 5-year survival in the latest series at 95% {753}.114 Well differentiated liposarcoma. 4. According to the AFIP files. Low grade leiomyosarcomas have a good prognosis. Some superficial haemangiomas. A Well differentiated liposarcoma is recognized by significant nuclear atypia in the adipocytes B The sclerosing variant of well differentiated liposarcoma has a dense collagenous background.113 Paratesticular liposarcoma toma-like tumour is a distinctive benign tumour occurring in the scrotum or inguinal region of older men. whereas alveolar RMSs are unfavourable. is typically AIDS associated. The most common sarcomas of the scrotum in adults are liposarcoma and leiomyosarcoma {252. can bleed {2578}. in our experience some tumours historically diagnosed as the latter actually represent dedifferentiated liposarcomas.112 Liposarcoma. subcutaneous smooth muscle zone. These tumours occur in children of all ages. Liposarcoma and MFH occur predominantly in older men. Clinical features Signs and symptoms A small proportion of scrotal soft tissue tumours occur as cutaneous or subcutaneous masses. dedifferentiated liposarcomas also tend to have a protracted clinical course with local recurrences. Spindle cells rhabdomyosarcomas are prognostically very favourable. 274 Tumours of the testis and paratesticular tissue . whereas high grade tumours often develop metastases and have a significant tumour related mortality. but most scrotal tumours are deep seated. malignant tumours are more likely to be symptomatic. and in our experience. Most paratesticular rhabdomyosarcomas are localized (stage. Fig. There are no large series on paratesticular liposarcomas. 4. but they are most common in young adults. Rare benign lesions of scrotum reported in infants and children include fibrous hamartoma of infancy. The mass contains fat density tissue (similar to the subcutaneous fat in the thigh) making the diagnosis of liposarcoma possible (short arrow). and 75% of these tumours are diagnosed between the ages of 50-80 years.111 Angiomyofibroblastoma-like tumour (closely related to cellular angiofibroma) contains abundant dilated vessels with hyalinized walls surrounded by bland spindle cell proliferation. often designated as angiokeratomas. although distant metastases may also occur. the amount of myxoid matrix varies.769. Nearly a third of them are diagnosed between the ages of 15-19 years and 86% are diagnosed before the age of 30. large. However. Superficial smooth muscle tumours may arise from the tunica dartos. A B Fig. liposarcomas and malignant fibrous histiocytomas (MFH) have similar age distribution. Fig. calcifying fibrous pseudotumour and lipoblastoma. asymptomatic or mildly uncomfortable masses. Benign lesions may present as slowly enlarging. Kaposi sarcoma is rare in the scrotum. The most common malignant tumour of the scrotum in children is paratesticular embryonal rhabdomyosarcoma. and have a history of rapid growth. tumours that have disseminated (group/stage 4) have a 6070% 5-year survival.Fig. In general.

but lipomas are generally smaller and more homogeneous. but are not required for diagnosis.e. Fig. Multivacuolated lipoblasts may be present. their extent is better demonstrated by CT and MR imaging rather than ultrasound. Our review of potential male cases in the AFIP files did not reveal any diagnostic examples of this entity. Fig. Mitotic activity is very low. which can often be traced back to the inguinal canal. 4.801}. complex. Distinctive at low magnification are prominent. the latter has raised a question whether these tumours are fatty related neoplasms. fat will appear very low density similar to subcutaneous fat. Some of these tumours arise from the tunica dartos {1886. Tumours of paratesticular structures 275 . such as the male angiomyofibroblastoma-like tumour. a tumour that typically occurs in women. Leiomyosarcomas are typically composed of spindled cells with often elongated. T2-weighted. lobulated soft to rubbery mass. and hernias are elongated masses. Benign lipomas and hernias containing omentum are potential mimics. CD34 and estrogen and progesterone receptors.116 Leiomyosarcoma of spermatic cord shows intersecting fascicles composed of atypical smooth muscle cells with blunt ended nuclei. CT and MR imaging are much more specific with fat being easily recognized with both modalities {372.115 Leiomyosarcoma. which are often hyperechoic by ultrasound. Larger tumours often have hyalinization.2406}.118 Embryonal rhabdomyosarcoma. Histopathology Haemangiomas are classified according to the vessel type. A normal testis is seen within the right hemiscrotum (arrow). By CT.2649}. the sonographic appearance of these tumours is variable and nonspecific.117 Paratesticular rhabdomyosarcoma. Additionally a fat suppressed imaging sequence should be performed for confirmation. It is displacing the base of the penis to the right (black arrow). Presence of significant nuclear atypia in adipocytes is decisive. Nuclear palisading may occur. blunt ended nuclei and variably eosinophilic. The tumour cells are immunohistochemically variably positive for desmin. 4. The latter features a superficial. mature fat. dilated blood filled spaces initially associated with the epidermis. Male angiomyofibroblastoma-like tumour is grossly circumscribed.With the exception of liposarcoma. MR image shows a large heterogeneous mass filling the left hemiscrotum and extending into the inguinal canal. but the presence of prominent atypia should lead to a careful search for mitotic activity or coagulation necrosis which are features of leiomyosarcoma. It seems likely that many tumours originally reported as male aggressive angiomyxomas. 4. large vessels with perivascular fibrinoid deposition or hyalinization. none of the other sarcomas can be differentiated from one another radiologically. these two processes are not considered synonymous {1442}. Leiomyomas are composed of mature smooth muscle cells. turn dark) on this sequence. Aggressive angiomyxoma. On MR imaging the fat in a liposarcoma will follow the signal intensity of surrounding fat on all imaging sequences. Fibrous hamartoma of infancy is a subcutaneous lesion composed of streaks of fibroblasts. However. Dedifferentiation to spindle cell “fibrosarcoma-like” or pleomorphic “MFH-like” phenotype occurs in a proportion of paratesticular liposarco- Fig. but is often low. Fat will lose signal intensity (i. The tumour cells between the vessels are tapered spindled cells with limited atypia. Imaging Liposarcomas generally present as large extratesticular masses. Great majority of liposarcomas are well differentiated with various combinations of lipoma-like and sclerosing patterns. paucicellullar fibroblastic tumefaction that typically contains scattered psammomatous calcifications and a patchy lymphoplasmacytic infiltration. Focal nuclear atypia may occur. 4. Granular cell tumours of the scrotum may be multifocal and are similar to those elsewhere in the skin. Focal epithelioid change is present in some cases. separated by fine collagen fibers. and spherical clusters of primitive mesenchymal cells {2096}. They all tend to be large. solid masses {372}. and a fatty component may be present. The level of mitotic activity varies widely. Although some similarities with angiomyofibroblastoma of female genitalia have also been noted. muscle actins. sometimes clumpy cytoplasm. Calcifying fibrous (pseudo)tumour is a densely collagenous. Capillary and cavernous haemangiomas are most common within the scrotum. Coronal. occur. Because of their large size. has been reported in men {1162. whereas angiokeratoma is the most common cutaneous vascular lesion {2578}. Areas with round cell or pleomorphic morphology may Fig. showing varying degrees of hyperkeratosis. myxoid change and calcification. Typical nuclear positivity for MyoD1. represent other entities. This tumour is probably analogous to cellular angiofibroma as reported in females. in fact.

A B Fig. they are not required for the diagnosis.1563.2146}. This type has been referred to as spindle cell or leiomyosarcoma-like rhabdomyosarcoma {1483}. Diagnostic confirmation should be obtained by immunohistochemistry. A Embryonal rhabdomyosarcoma can have a well differentiated pattern with abundant rhabdomyoblasts. Malignant fibrous histiocytoma and fibrosarcoma are diagnoses by exclusion. However. with some resemblance to smooth muscle cells. hyperchromatic oval cells. The dedifferentiation may occur at the inception or in a recurrent tumour. especially in the spindle cell rhabdomyosarcoma. A typical example of embryonal rhabdomyosarcoma contains large number of primitive round to oval cells and smaller numbers of differentiating rhabdomyoblasts with eosinophilic cytoplasm and possible cytoplasmic cross striations. Myxoid matrix is often present. Some liposarcomas of the scrotum can have smooth muscle elements. but a small percentage (10-15%) have been classified as the alveolar type in the largest clinicopathological series {753. Although cytoplasmic cross striations may be noted. the number of differentiating rhabdomyoblasts varies widely. Post chemotherapy specimens can show extensive rhabdomyoblastic differentiation. This component can give rise to metastases. these have been designated as combined lipoleiomyosarcomas {2539}. and the latter has a more uniform spindle cell pattern. mas {1076}. Virtually all RMS are positive for desmin and muscle actins (HHF35).119 Embryonal rhabdomyosarcoma. MyoD1 and myogenin (the latter demonstrated with Myf4 antibody). 276 Tumours of the testis and paratesticular tissue . Cytoplasmic positivity for MyoD1 occurs in various tumours and has no diagnostic significance.1283. The former is a pleomorphic fibroblasticmyofibroblastic sarcoma. A rare variant of embryonal rhabdomyosarcoma is composed of predominantly spindled cells. B Embryonal rhabdomyosarcoma may be composed of primitive. and most have nuclear positivity for myogenic regulatory proteins. The majority of paratesticular rhabdomyosarcomas are of the embryonal type. 4.

melanoma.2663. Secondary tumours 277 . but one third have been under age 40 {1042. colon and kidney in descending order of frequency. This example. to be the more common ones {548.2664}. 2664}. Macroscopy The cut surface shows one or more nodules of tumour or a solitary diffuse mass. The excess of prostate cases is doubtless related to the routine examination of orchiectomy specimens from patients with prostate carcinoma {2663}.2664}.Secondary tumours C. accounting for 2. Histopathology The tumour exhibits an interstitial growth pattern with preservation of tubules and only uncommonly does tumour involve tubular lumina.1691.120 Atrophy and metastatic carcinoma from prostate (bilateral orchiectomy). Origin of metastasis A multitude of tumour types have metastasized to the testes. lung. Bilaterality has occurred in 1520% {548. It is most often found at autopsy in patients with known disseminated disease or after orchiectomy for prostatic carcinoma {1691}. Incidence This is one of the most uncommon causes of testicular tumour. but in 6-7% of cases it has presented as the initial evidence of disease as a palpable mass {548. Fig. A Metastatic lung carcinoma. A B Fig. including some sarcomas but most studies have found prostate.J. Vascular invasion is usually a prominent feature. Davis Definition Tumours of the testis which do not originate in the testis or result from direct extension of tumours arising in adjacent intrascrotal sites.2664}. shows luminal involvement. unlike most metastatic tumours. B Metastatic prostatic carcinoma with PSA reactivity.122 Secondary tumours of the testis. with a mean of 55-57. 4.4-3.121 Metastatic carcinoma from prostate in epididymis. Clinical features Most patients are over age 50. 4. 2664}. 4.6% {1800. Fig.

A Metastatic malignant melanoma. larynx. urethra. neuroblastoma B Fig. sphenoid sinus. renal pelvis.123 Secondary tumours of the testis. ethmoid sinus.05 Secondary tumours of the testis (surgical cases) Primary Prostate Renal cell carcinoma Melanoma Lung* Bladder Carcinoid Pancreas Gastrointestinal Neuroblastoma Others** Total cases Total 67 24 14 8 5 3 2 2 2 8 135 % 50% 18% 10% 6% 4% 2% 1% 1% 1% 6% 100% * Includes 4 small cell type ** One each: Thyroid. colon.06 Secondary tumours of the testis (autopsy cases) Primary Lung* Melanoma Prostate Pancreas Others** Total cases Total 13 6 3 3 5 30 % 43% 20% 10% 10% 17% 100% * Includes 5 small cell type ** One each: thyroid. A Table 4.Table 4. B Metastatic malignant melanoma with HMB45 reactivity. 4. PNET. 278 Tumours of the testis and paratesticular tissue . nephroblastoma. Merkel cell tumour. adrenal.

with the highest burden in some developing countries. many patients are treated in late stages of the disease. Non-viral infections due to poor hygienic conditions are also established risk factors and this is underlined by the rare occurrence of penile cancer in circumcised men. . particularly in Africa and South America. Chronic papillomavirus infections have been identified with increasing frequency. However.CHAPTER 5 Tumours of the Penis The incidence of penile cancer varies worldwide. leading to the necessity of extensive surgical intervention. Metastasis is uncommon. This indicates that environmental factors play an important role. Well differentiated squamous cell carcinomas prevail.

uicc.WHO histological classification of tumours of the penis Malignant epithelial tumours of the penis Squamous cell carcinoma Basaloid carcinoma Warty (condylomatous) carcinoma Verrucous carcinoma Papillary carcinoma.2662}.org/tnm/ 280 Tumours of the penis . Behaviour is coded /0 for benign tumours. 8077/2 8081/2 8080/2 8542/3 8720/0 8720/3 TNM classification of carcinomas of the penis TNM classification 1. and /1 for borderline or uncertain behaviour. /3 for malignant tumours. N1. unilateral or bilateral Tis Ta T1 T1 T2 T1. /2 for in situ carcinomas and grade III intraepithelial neoplasia. T2 T3 T4 Any T Any T N0 N0 N0 N1 N0.org).N1 N2 N0. N2 Any N N3 Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M1 __________ 1 {344. 2 A help desk for specific questions about the TNM classification is available at http://www. NOS Sarcomatous carcinoma Mixed carcinomas Adenosquamous carcinoma Merkel cell carcinoma Small cell carcinoma of neuroendocrine type Sebaceous carcinoma Clear cell carcinoma Basal cell carcinoma 8070/31 8083/3 8051/3 8051/3 8050/3 8074/3 8560/3 8247/3 8041/3 8410/3 8310/3 8090/3 Precursor lesions Intraepithelial neoplasia grade III Bowen disease Erythroplasia of Queyrat Paget disease Melanocytic tumours Melanocytic nevi Melanoma Mesenchymal tumours Haematopoietic tumours Secondary tumours __________ 1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {808} and the Systematized Nomenclature of Medicine (http://snomed.2 T – Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ Ta Non-invasive verrucous carcinoma T1 Tumour invades subepithelial connective tissue T2 Tumour invades corpus spongiosum or cavernosum T3 Tumour invades urethra or prostate T4 Tumour invades other adjacent structures M – Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping Stage 0 Stage I Stage II Stage III Stage IV N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single superficial inguinal lymph node N2 Metastasis in multiple or bilateral superficial inguinal lymph nodes N3 Metastasis in deep inguinal or pelvic lymph node(s).

a decline commonly speculated to be due to improved personal hygiene. Tumours of pendulous urethra are discussed under urothelial neoplasms. {2016}. Reuter G.L. from the preputial orifice to the fossa navicularis. Fig. coronal sulcus and foreskin {2905}.1590. Malignant epithelial tumours 281 . In the foreskin additional levels are DT= dartos and F= skin. Anatomical features: cut surface view of a partial penectomy showing anatomical sites. Cubilla J.01 Anatomy of the penile structures.0/100. ultraviolet irradiation. sarcomas (excluding Kaposi sarcoma) prefer the corpora. history of warts. The fossa navicularis represents the 5-6 mm of the distal penile urethra but its squamous lining is continuous with that of the perimeatal glans. Ayala V.02 Penis: ASR world. GL= glans and COS= coronal sulcus. The incidence of penile cancer is highly correlated to the incidence of cervical cancer {280}. LP= lamina propria. Horenblas A. The penile fascia covers the shaft and inserts into the lamina propria of the coronal sulcus {171}. 300-fold less. coronal sulcus and glans. CS= Corpus Spongiosum and CC= corpus cavernosum. per 100. The tunica albuginea (ALB) separates CS from CC. Age standardized incidence rates in the Western world are in the range of 0. Fig.000. 5. The lamina propria (LP) is similar for all sites but deeper anatomical levels are different: in the glans there are the corpus spongiosum (CS). or condylomas and lack of circumcision {620.000 {2016}. Benign and malignant soft tissue tumours are unusual. From D.1187. Penile fascia (PF) encases CC. 1871. but a large variety occurs in the penis. chronic inflamma- tory conditions. Dillner P. smoking. Parkin et al. Schellhammer S. with the highest cumulative rates (1% by age 75) seen in parts of Uganda and the lowest.1069. Topographic definition of penile mucosa and anatomical levels Penile mucosa includes the inner surface of the foreskin. The urethra is ventral and distally shows the meatus urethralis (MU). SCC of the skin of the shaft are less frequent {695} than melanomas or Paget disease. The anatomical levels in the glans are E= epithelium. all ages. M. Incidence of penile cancer in some regions worldwide. 5. dermis and epidermis. F= foreskin. An earlier age at onset and a higher proportion of younger patients are seen in high incidence areas.G.2507}. Incidence The incidence rates of penile cancer vary among different populations. especially lichen sclerosus.1058. There is a continuous increase with advancing age. tunica albuginea (TA) and corpus cavernosum (CC) and in the foreskin the dartos. Etiology Etiological factors associated with penile cancer are phimosis.E. found among Israeli Jews. Von Krogh Introduction The vast majority of malignant tumours are squamous cell carcinomas (SCC) and they occur chiefly in the squamous epithelium of the glans. The incidence rates have been slowly declining in some countries since the fifties {1607}.Malignant epithelial tumours A. Whereas carcinomas affect mainly the distal penis or glans.F.3-1.

Rubin et al. In patients with long foreskin and phimosis the tumour may be concealed and an inguinal metastasis be the presenting sign. and a multiple HPV type infection: lane 3: HPV 45 and 70.2258}.0 Multiple HPV n 0 6 6 8 0 1 1 0 0 0 10 %* 0 22.7 80. 5. has played a minimal role in the staging and direction of treatment options. a recurrent tumour in the surgical stump or a large primary tumour with inguinal nodal and skin metastases.03 HPV-typing in penile cancers.6 62. initially to superficial lymph nodes. Human papillomavirus (HPV) infection HPV is present in a subset of penile SCC. until very recently. Exophytic growth pattern.0 91.4 21. Penile intraepithelial neoplasia (IN). Tumour spread Penile carcinoma has a fairly predictable dissemination pattern. Lymphoscintigraphy visualized at least 1 sentinel node in 98% of the patients. {2258}. HPV-positive Diagnosis Condyloma Dysplasia All benign cases Keratinizing SCC Verrucous SCC Basaloid SCC Warty SCC Clear cell SCC Sarcomatoid SCC Metastatic SCC All cancer cases n 12 30 42 106 12 15 5 2 1 1 142 n 12 27 39 37 4 12 5 1 0 1 60 % 100. Some tumours metastasize directly to deep inguinal nodes. Note: HPV 18 is reactive with two probes.5 41.0 70.1153}. a recognized precursor.0 0 25.6 0 8. Imaging by lymphoscintigraphy with a radioactive tracer is considered as one of the prerequisites to determine the individual drainage pattern in order to find the sentinel node.0 100. Identification of HPV genotypes using a linear probe assay.0 100. is consistently HPV DNA positive in 70-100% of investigated cases {1153}.3 43.3 20.0 0. Clinical features Signs and symptoms Mean age of presentation is 60 years {517.0 100. Skip inguinal nodal metastases 282 Tumours of the penis .7 18. and HPV 45 with probes 45 and 45/68.6 Imaging Imaging. with HPV 16 as the most frequent type Table 5. Recently the concept of sentinel node {356} has been explored again in penile cancer {2579}.0 0 0 0 0 0 1.1 50.0 42. HPV DNA is preferentially found in cancers with either basaloid and/or warty features. lane 2: HPV 18. Fig. but from unrecognized HPV-negative precursor lesions. 5. This pattern presents in about 70 % of the cases.2 Low risk HPV n 11 5 16 0 1 0 0 0 0 0 1 %* 91. From Rubin et al. B Squamous cell carcinoma of the usual type.A B Fig. {945.0 50.A. {2258}.6 High risk HPV n %* 1 16 17 23 2 11 4 1 0 1 42 8. Reprinted with permission from M. A possible explanation is that the HPV-negative invasive cancers do not arise from the HPV-positive IN.0 0 100.0 92. and only weakly correlated with typically keratinizing SCC {945.9 33.8 34.3 80. MRI can be useful to determine the true proximal extent of the tumour. dysplasia and carcinoma. ultrasound investigation and magnetic resonance imaging (MRI) {1535} and found physical examination as the most accurate method to determine tumour site and extent of corpus spongiosum infiltration. A recent study compared the accuracy of physical examination. LiPA strips with hybridization bands indicating a single HPV type infection: lane 1: HPV 16.2905} and patients may present with an exophytic or flat ulcerative mass in the glans.0 0 0 0 16.04 A.01 HPV DNA detection in penile condyloma. The first metastatic site is usually a superficial inguinal lymph node located in the groin upper inner quadrant (sentinel node). Occasionally the lesions may be subtle.0 90. such as a blemish or an area of erythema. 18 and c68. then to deep groin and pelvic nodes and lastly to retroperitoneal nodes. Because of the possibility of imaging in various planes and because of the ability to visualize other structures of the penis.2 15.3 59.

from distal glans (GL). lungs and bone {2905}. B Squamous cell carcinoma. Squamous cell carcinoma Definition A malignant epithelial neoplasm with squamous differentiation. appeared to be an independent risk factor for nodal metastasis. histological type. 1608. tumour size. (ALB) tunica albuginea. Large neoplasm replacing glans surface. Ploidy was not found to be useful as a predictor of prognosis {1002}.06 Routes of local spread: Lines and arrows depict pathways of local tumour (CA) progression. Malignant epithelial tumours 283 . carry a better prognosis {1933} because of low grade and frequent superficially invasive growth {514}. Prognosis Pathologic factors related to prognosis of penile carcinomas are site of primary tumour. heart. foreskin (F) and coronal sulcus (COS) to proximal corpus spongiosum (CS). HPV was not found to be prognostically important {236}. however. The incidence of metastasis in verruciform tumours is minimal.A B C Fig. Tissue associated eosinophilia has been linked with improved survival in patients with penile cancer {1961}. CS and CC in glans and LP. Measurement of depth of invasion in mm should be performed from the basement membrane of adjacent squamous epithelium to deepest point of invasion {693}. dartos and skin in the foreskin). Common general sites of metastatic involvement are liver. The 3 most important pathological factors to predict final outcome are histological grade.1640}. LP. progression of disease and survival in 2 studies {1546. Three main growth patterns are noted: superficially spreading with horizontal growth and superficial invasion. penile fascia (PF). depth and vascular invasion. 5. Macroscopy Average tumour size varies from 3 to 4 cm. C Squamous cell carcinoma.2458}. including micrometastasis {1672.2438}. depth of invasion and vascular invasion especially the combination of grade and depth. Massive replacement of penile corpus spongiosum and cavernosum by a white neoplasm. grade. The threshold for penile metastasis is about 4-6 mm invasion into the corpus spongiosum {520}. corpora cavernosa (CC). 5. Mortality in patients with superficially spreading carcinomas is 10% compared with 67% for patients with vertical growth pattern {521}. There is no consensus regarding method of grading {1121. The depths of invasion should be evaluated on penectomy specimens {2719}. ICD-O codes Squamous cell carcinoma Basaloid carcinoma Warty (condylomatous) carcinoma Verrucous carcinoma Papillary carcinoma (NOS) Sarcomatoid (spindle cell) carcinoma Adenosquamous carcinoma 8070/3 8083/3 8051/3 8051/3 8050/3 8074/3 8560/3 Fig. One system utilizes a prognostic index from 1 to 6. (primary tumour to pelvic inguinal nodes) are extremely unusual. Evaluation of the anatomical levels of tumour invasion is limited by the variation in thickness of the corpus spongiosum.05 A Well differentiated squamous cell carcinoma with invasion of corpus spongiosum. Low indices (13) are associated with no mortality. Metastatic and mortality rates are high in patients with indexes 5 and 6 {519}. pattern of growth. Molecular markers have been studied as prognostic predictors. Tumours exclusively in the foreskin. skin and urethra (U). The large destructive lesions or bulky exophytic tumours especially those of the verruciform group should be measured from the nonkeratinizing surface of the tumour to the deepest point of invasion. more than one method should be utilized. P53. combining numerical values for histologic grade (13) and anatomical level of invasion (1-3. Systemic blood borne dissemination occurs late. A combination of histologic grade and depth is thought to better predict metastasis and mortality. When possible.

08 A Squamous cell carcinoma. The glans surface may be flat. 5. Invasion can be as individual cells. granular irregular masses partially or totally replacing the glans or foreskin. Most frequently there is keratinization and a moderate degree of differentiation. Adjacent hyperplastic or precancerous lesions often can be visualized as a marble white 1-2 mm thickening. Multiple urethral sites may be involved at the resection margins {2720}. This is the characteristic spread of superficially spreading carcinomas. C Well differentiated keratinizing SCC.09 Squamous cell carcinoma of the penis. The contrast between the pale invasive tumour and the dark red colour of CS or CC permits determination of the deepest point of invasion. Penile SCC may spread horizontally and externally to skin of the shaft and internally to proximal urethral margin of resection. The tumours are usually white. small irregular nests of atypical cells. pubic or scrotal skin. B Clear cell carcinoma. grade 1. Pagetoid intraepithelial spread may simulate carcinoma in situ or Paget disease. 5. Tumour in the fascia may secondarily penetrate into corpus cavernosum via nutritional vessels and adipose tissue traversing the tunica albugina. Multicentric carcinomas are more frequent in the foreskin {1933}. A B C Fig. An important. B Squamous cell carcinoma infiltrating periurethral glands. In some patients the foreskin is abutted by underlying tumour and may show skin ulcerations. a common site of positive surgical margin of resection. Any combination may occur {517}. A An irregular granular flat neoplasm involving the mucosal aspect of the foreskin. grey. Histopathology There is a variable spectrum of differentiation from well to poorly differentiated. frequently associated with regional metastasis. which is prognostically important {520}. A B Fig. The vertical spread may progress from surface to deep areas {517}. Typically. It is not unusual to find "satellite nodules". under recognized route of spread is the penile fascia. Infrequently (about a fourth of cases) the corpus cavernosum is affected. Mixed tumours should be suspected when different growth patterns are present. vertical growth deeply invasive and multicentric. 5. ulcerated or 284 Tumours of the penis .deformed by an exophytic mass. cords or large cohesive sheets present in the lamina propria or corpus spongiosum. foreskin carcinomas spread to coronal sulcus or glans and carcinomas originating in the glans may spread to the foreskin. The boundaries A B Fig. The fascial involvement in tumours of the glans is usually through the coronal sulcus.07 . Local spread Penile tumours may spread from one mucosal compartment to the other. A Squamous cell carcinoma infiltrating urethra. Very well differentiated and solid nonkeratinizing poorly differentiated carcinomas are unusual.Squamous cell carcinoma. a poorly differentiated squamous cell carcinoma with cytoplasmic clearing. B Well differentiated SCC with irregular infiltrating borders. In more advanced cases penile carcinomas may spread directly to inguinal.

Median age at presentation is in the sixth decade. including corpora cavernosa. show keratinization.10 Squamous cell carcinoma. The papillae have thin fibrovascular cores and the tips are variably round or tapered. Hyperplastic nests do not involve the dartos or corpus spongiosum. grade 3. A Poorly differentiated keratinizing SCC. Tumours as large as 5.521.0 cm have been described. They tend to infiltrate deeply into adjacent tissues. which is firm. Variants of squamous cell carcinoma Basaloid carcinoma Basaloid carcinoma is an HPV related aggressive variant. B Squamous cell carcinoma of the penis. Superficially invasive tumours tend to be well differentiated and deeper tumours poorly differentiated. often associated with comedo-type necrosis.522. Spread to inguinal lymph nodes is common and the mortality rate is high. basaloid or clear cells. are more eosinophilic and nucleoli are prominent. Most commonly it arises in the glans. it presents as a flat. acantholytic. between stroma and tumour are irregular or finger like. In poorly differentiated tumours individual cell necrosis or comedo-like necrosis may be found as well as numerous mitotic figures {521. Microscopically. it has a hyper-parakeratotic arborizing papillomatous growth. Stromal or desmoplastic reaction may be present in both conditions but is more frequent in A B Malignant epithelial tumours 285 Fig. Deeply invasive carcinomas may focally show spindle.945}.945}. The tumour cells have low to intermediate grade cytology. coronal sulcus or foreskin. upper right. Grossly. Broadly based margins are unusual.11 A Basaloid carcinoma of the penis. Koilocytotic atypia is con- Differential diagnosis Superficial and differentiated invasive lesions should be distinguished from pseudoepitheliomatous hyperplasia. carcinomas. Mitotic rate is usually brisk. pleomorphic. . In SCC the nests detached from overlying epithelium are disorderly. cauliflower-like lesion that may involve glans.2905}. Grossly. The cells are small with scant cytoplasm and oval to round. 5.A B Fig. ulcerated and irregular mass. it is composed of packed nests of tumour cells. 5. which accounts for 510% of penile cancers {518. Palisading at the periphery of the nest and abrupt central keratinization is occasionally seen. Median age is in the fifth decade.523. tan and infiltrative. giant. Microscopically. B Basaloid carcinoma of the penis with comedo necrosis. Warty (condylomatous) carcinoma This variant corresponds to 20% of "verruciform" neoplasms {235. it is a white to tan. hyperchromatic nuclei and inconspicuous nucleoli.

Microscopically. Verrucous carcinoma This variant usually involves the glans or foreskin {1232. The nuclei are bland. The interface Fig.14 Verrucous carcinoma. The glans is a frequent site {2838} but they may occur in the foreskin as well.12 A Warty (condylomatous) carcinoma of the penis. Note papillary growth. Grossly. these are well differentiated. Histologically. after a recurrence.C Warty squamous cell carcinoma. 5. On cut surface.A B C Fig. Differentiated carcinoma in situ or invasive carcinoma is usually found. bone and cartilage. Hyperkeratosis and papillomatosis. Tumours may extend into the underlying stroma with a broad based.15 Mixed verrucous-squamous cell carcinoma. with the underlying stroma is infiltrative and irregular. Fig. not otherwise specified (NOS) This variant occurs mainly in the fifth and sixth decades {521}. it is exophytic. Fig. B. hyperchromatic and wrinkled and binucleation is common. Sarcomatoid (spindle cell) carcinoma Squamous cell carcinoma with a spindle cell component arises de novo. Verrucous carcinoma is considered not to be HPV-related. round or vesicular. although slightly more atypical nuclei may be seen at the basal cell layer. Nuclei may be large. usually associated with deeply invasive lesions. regional lymph node involvement has not been seen in the relatively few cases reported. HPV DNA testing has demonstrated HPV 16 and 6 in some cases. 5. Microscopically. pushing border.0 cm have been reported. Some have metastasized to regional lymph nodes. Grossly. 5. Despite the fact that invasion into the corpus cavernosum and spongiosum has been documented.13 Verrucous carcinoma. grey-white and firm.5 cm and appears as an exophytic. 5.0 cm although cases as large as 14. grey-white mass. hyperkeratotic lesions with irregular. Koilocytotic changes are not evident. The papillations are of variable length and fibrovascular cores are inconspicuous. with or without fibrovascular cores. they are 5-7 cm irregular white grey mixed exophytic and endophytic masses. making determination of invasion difficult. Tumours may infiltrate deeply and the interface of tumour with stroma is usually irregular. 5. Predominantly papillomatous appearence except in the lower central area where the neoplasm is solid. corpus spongiosum and cavernosum are invariably involved. benign or malignant {103}. or following radiation therapy {821}. complex papillae. it meas- ures about 3. Fig. spicous. Electron microscopy and immunohistochemistry are useful to rule out sarcomas and spindle cell Papillary carcinoma.1643}. The tumour pushes into corpus spongiosum with focal involvement of tunica albuginea. malignant fibrous histiocytoma or leiomyosarcoma. there are atypical spindle cells with features similar to fibrosarcoma. 286 Tumours of the penis . it is a very well differentiated papillary neoplasm with acanthosis and hyperkeratosis.16 Adenosquamous carcinoma. This is a slow growing tumour that may recur locally but metastasis does not occur in typical cases. Grossly. These cells have the potential to differentiate into muscle. These tumours are not HPVrelated. The median size in one series was reported as 3.

19 Warty-basaloid carcinoma.1232}. and well differentiated squamous cell carcinoma with pseudohyperplastic features (pseudohyperplastic carcinoma) {524}.1674}. Sarcomatoid carcinomas are associated with a high rate of regional nodal metastases {521}.18 Sarcomatoid (spindle cell) carcinoma of the penis. The glands stain positive for CEA. The warty-basaloid carcinoma has a high incidence of groin metastasis {2574}.1642}.1455. Other rare pure primary carcinomas ICD-O codes Merkel cell carcinoma Small cell carcinoma of neuroendocrine type Sebaceous carcinoma Clear cell carcinoma 8247/3 8041/3 8410/3 8310/3 Basal cell carcinoma ICD-O code 8090/3 Adenosquamous carcinoma Squamous cell carcinoma with mucinous glandular differentiation arises from surface epithelium.1208. The localization is on the shaft and rarely on the glans {872. B Surface appearance.2702}.17 Low grade papillary carcinoma affecting the foreskin. noma {2905}. sebaceous carcinoma {1967}.2041}. glands {516. A moderate to high grade squamous cell carcinoma in an otherwise typical verrucous carcinoma (so called ‘hybridverrucous’) shows metastatic potential {473. small cell carcinoma of neuroendocrine type {830}. 5. B Malignant epithelial tumours 287 . melanomas {1613}.or multicentric {2041}.Fig. A Invasive nests. 5. it is a firm white grey irregular mass involving the glans. It is impor- A Fig. Adenocarcinomas and mucoepidermoid carcinomas of the penis have also been reported {810. the squamous predominates over the glandular component. Mixed carcinomas About a fourth of penile carcinomas consist of a mixture of various types. BCCs are differentiated and usually superficial with minimal metastatic potential {1317}. Grossly.1425. They may be uni. Another rare lesion is the papillary basaloid carcinoma consisting of an exophytic growth. 2 were in the penis {1244}. Fig. Microscopically. The origin may be related to misplaced or metaplastic mucinous A small number of unusual primary penile neoplasms include the Merkel cell carcinoma {2625}. clear cell carci- Basal cell carcinoma (BCC) is a rare indolent neoplasm of the penis identical to BCC of other sites {794. 5. with papillae composed of small poorly differentiated cells similar to the cells seen in invasive basaloid carcinomas {515}. Other recognized combinations include adenocarcinoma and basaloid {515} (adenobasaloid) and squamous and neuroendocrine carcinoma. Of 51 BCC of regions not exposed to sun.

About 30 sexually transmittable genotypes exist that are further classified into "low" and "high risk" types according to oncogenic potential {574. Precursor lesions HPV and penile intraepithelial neoplasia ICD-O code Intraepithelial neoplasia Grade III 8077/2 Human papillomaviruses (HPV) are the most heterogeneous of human viruses {574}. phimosis and poor hygiene may be important contributing factors {670. Fig. crusting. Bowenoid papulosis and Bowen disease.20 Bowenoid papulosis. It is characterized by a semi-malignant slowly growing condylomatous growth often larger than 288 Tumours of the penis . Most patients with IN lack physical symptoms. SCC is thought to develop via HPV-associated precursor lesions (intraepithelial neoplasia. a vigilant approach to diagnostic biopsy sampling cannot be overly stressed. has abrupt keratinization. being rare in the USA and Europe but fairly common in many developing countries {619. bleeding.including types 6 and 11.2756}. 5. A pathogenic role of chronic lichen sclerosus and verrucous carcinoma has been discussed. tant to distinguish them from the aggressive basaloid squamous cell carcinoma. while oncogenic HPVs have been linked more strongly to warty/basaloid carcinomas {945}. They are accompanied by loss of polarity. The predominant HPV that is found in penile SCC is type 16. followed by type 18. 5. Mucosal infections mainly are transient in young people {670}. Bowen disease appearing as a well demarcated reddish plaque on the inner aspect of the foreskin. IN) that are graded I-III in proportion to the epithelial thickness occupied by transformed basaloid cells. Chronic inflammation. Due to clinical overlap and differential diagnostic problems. the IN occupies the lower one third. The lesions may be multiple or solitary and the diameter varies from 2-10 mm. and in grade III the full epithelial thickness ("Bowen atypia". Condylomas and IN sometimes coexist as part of a morphological continuum. overt genital warts ("condylomas") are associated with "low risk" HPVs . These vary in size and shape. two types exist. Longitudinal studies demonstrate that patients who cannot clear high risk HPV infections within about a year are at risk for malignant transformation. B Clinically. macular and papular (right).are predominantly associated with subclinical lesions {2756}. Generally. but itching. HPV types 6/11 have been detected in anecdotal cases. The "high risk" HPVs . Concurrent infection with low and high risk types is common. in situ SCC). Fig. Giant condyloma "Giant condyloma" (Buschke-Löwenstein) is a rare (about 100 cases published) and peculiar condyloma variant {968.A B Fig. in grade II the lower two thirds.2754-2756}. which invades deeply. comedo necrosis and high mitotic rates. A.22 High grade squamous intraepithelial lesion (SIL). In grade I. Studies of HPV and penile cancer are limited because of the scarce occurrence and the peculiar geographical distribution of this malignancy.2756} generally arising due to poor hygiene of uncircumcized men (range 18-86 years of age). with the nuclei being pleomorphic and hyperchromatic.21 Penile Bowen disease. pain. scaling and difficulty in retracting the foreskin may develop {2756}. The following comments summarize clinical features of three penile conditions presumed to be precancerous: Giant condyloma. 5.619}. squamous.most commonly types 16 and 18 . tenderness.

when the clinical presentation overlaps with that of BD. Typical spread of atypical cells in the epithelium. Typical IN III lesions tend to be small (2-10 mm). Fig. salmon-red. these lesions often show recalcitrance after surgical intervention. Occasionally they are ulcerative or may be covered by a pronounced hyperkeratosis that may appear as a "cutaneous horn" {2756}. Both conditions sometimes resemble lichen sclerosus. However. Oncogenic HPV DNA. greyish-white lesions in the preputial cavity. ranging in diameter from a 2-35 mm. multicentric smooth velvety maculopapular reddish-brown. most commonly the glans. From the records of 87 men with BD.24 Paget disease. psoriasis and eczema {2756}. most commonly is type 16. basaloid. verrucous carcinoma and warty carcinoma. The average age on diagnosis of BD/QE is 61 years. 5. Possibly. documented transformation to SCC has been reported in the range of 533% in uncircumcized men {2756}. mixed tumours have been observed in which unequivocal features of benign condyloma. spontaneous regression within a year has been reported in immunocompetent individuals below the age of 30 years. BP may also be solitary or coalesce into plaques. with areas of benign condyloma intermixed with foci of atypical epithelial cells or even well differentiated in situ carcinoma. some cases of persistent BP may progress to BD and invasive cancer. Reddish-brown and pigmented colour tones are more common than in benign condylomas. 84 were uncircumcized and Malignant epithelial tumours 289 . Thicker epithelial lesions may be ashen-grey or brownish-black. 5.23 High grade squamous intraepithelial lesion (SIL). BP is predominantly transient. self limiting and clinically benign in young people. The term has been used for various lesions namely: true giant condylomas. the clinical appearance is that of a single. The histopathological presentation cannot be distinguished from that of Bowen disease (BD) although focal accumulations of uniformly round nuclei and perinuclear vacuoles in the horny layer is more common in BP {968}. Bowen disease (BD) has long been considered a premalignant lesion.5 cm in diameter. well demarcated reddish plane and/or bright red scaly papule or plaques. but types 18 and/or 33-35 have repeatedly been discovered. Usually. Genital Bowenoid papulosis (BP) is the term used for lesions in young sexually active people16-35 (mean 28) years of age that display histological features of IN III. Bowenoid papulosis and Bowen disease ICD-O codes Bowen disease Erythroplasia of Queyrat 8081/2 8080/2 Fig. Moreover. Lesions on dry penile skin are brownish-red or pigmented. The sharp border between the epidermis and the dermis is preserved. Review of 100 cases of QE revealed that 90% of cases were white men with a median age of 51 years. The accurate diagnosis may require multiple biopsies. In some cases a complex histological pattern exists. warty carcinoma and either basaloid or typical squamous cell carcinoma occur adjacent to one another {2756}. The most important clinical hallmark in the differential diagnosis versus BP is the age. If left untreated. When located on the glans penis it is by tradition named erythroplasia of Queyrat (EQ). It is currently believed that the giant condyloma and verrucous SCC are separate pathological lesions.

the median age of patients with BD is 51 years {2756}. perineal or perianal tumour. Therefore we advocate that in persons older than 40 years. but a clinical followup at 3 and 12 months seems reasonable to confirm clearance and healing. Patients remain at risk after penis sparing therapy and should be instructed to come back as soon as possible in case of suspected recurrence including the experience of a "lump". Invasion into the dermis may result in metastasis to groin or widespread dissemination {1744}. but exclusive penile lesions occur {1586}.1417}. CEA. 1401. a year or so of watchful waiting may be justified. 290 Tumours of the penis . Prognosis and follow-up of IN It is clinically impossible to determine which individual will develop pernicious HPV infection and progress from IN III to invasive cancer. lesions should always be considered as premalignant and treated surgically. primary in the epidermis or spread from an adenocarcinoma {1067. Frequently positive stains in PD are mucins. as well as in immunosuppressed individuals at earlier ages (including HIV infected people and allograft recipients). In younger men. or the occurrence of local symptoms. inguinal.three had been circumcized by 9 years of age. there is an intraepithelial proliferation of atypical cells with a pale granular or vacuolated cytoplasm. Paget disease ICD-O code 8542/3 This is a form of intraepidermal adenocarcinoma. Microscopically. The skin of the shaft is usually involved as part of a scrotal. A variety of treatments have been used. the duration of follow-up is uncertain. Treatment failure may be related to indistinct margins (marginal recurrences). low molecular weight cytokeratins. EMA. extension of IN down hair follicles and unrecognized foci of invasive tumour. Paget disease (PD) should be distinguished from pagetoid spread of penile or urothelial carcinomas {2624}. Clear cell papulosis {422} pagetoid dyskeratosis {2685} or mucinous metaplasia {2684} should also be ruled out. Following treatment. Nuclei are vesicular and nucleoli prominent. Bowen disease and melanomas. Patients are in the six or seventh decades and present with thickened red to pale plaques with scaling or oozing. gross cystic disease fluid protein and MUC 5 AC {1401}.

Epidemiology and etiology Penile melanoma affects white men. the presence of atypical melanocytes migrating to different levels of the epithelium makes it a melanoma in situ. brown. or nodule that is blue.G. the lesion has been described as an ulcer. A In this illustration there are scattered large atypical melanocytes involving all layers of the epithelium. and mucosal lentiginous. and the remainder arises from the skin of the shaft. with just over 100 cases of malignant melanoma reported since their first description by Muchison in 1859 {1229. Risk factors include pre-existing nevi. Prognosis and predictive factors Management is similar to melanomas of other regions. Histopathology Reported histologic subtypes include nodular. The Breslow level (depth of invasion) is an important determinant of overall survival. Melanocytic lesions 291 . papule. Tamboli Definition Melanocytic lesions of the penis identical to those in other sites. Perspective view of the atypical junctional component.1950}. between the ages of 50 and 70 years. Localization Sixty to eighty percent of melanomas arise on the glans penis.1439. Other melanocytic lesions include penile melanosis. ICD-O codes Melanocytic nevi Melanoma 8720/0 8720/3 Fig. or red. exposure to ultraviolet radiation. superficial spreading. Incidence Malignant melanocytic lesions of the penis are rare. Although the low power suggests a dysplastic nevus. and a history of melanoma. Macroscopy Grossly.25 Invasive melanoma. less than 10% affect the prepuce.26 Melanoma in situ. melanocytic nevi. atypical lentiginous hyperplasia. B This lesion shows an atypical junctional melanocytic proliferation associated with melanocytic cells that are present in the upper layers of the epithelium. genital lentiginosis. Ayala P.Melanocytic lesions A. and atypical melanocytic nevi of the acral/genital type. 5.1614. 5. A B Fig.

Among nerve sheath tumours of the penis. Myointimoma is a benign vascular related tumefaction with a myoid phenotype. granular cell tumours primarily affect individuals in the A 292 Tumours of the penis B Fig. neurofibromas have a peak incidence in the first and second decades.e. Most soft tissue tumours of the penis occur over a wide age range.28 A Lymphangioma of the penis. The presence of scattered lymphoid follicles is a helpful clue to the diagnosis. for the most part. and appears to be derived from. immunodeficiency states.. and neuropathology fascicles). The most common malignant mesenchymal tumours are Kaposi sarcoma and leiomyosarcoma.F. soft tissue. Incidence Mesenchymal tumours are very uncommon in the penis. Irradiation has been implicated in the pathogenesis of several sarcoma types.27 Angiokeratoma of the penis. especially malignant fibrous histiocytoma. 9120/0 9170/0 9540/0 9560/0 9580/0 8890/0 8711/0 8830/0 Epidemiology Factors predisposing individuals to the development of soft tissue tumours are. . and others. giant cell fibroblastoma. the vascular intima. this process is intimately associated with. poorly understood. With the exception of myointimoma. The most frequently encountered benign mesenchymal tumours of the penis are vascular related.412} have been implicated in the development of Kaposi sarcoma. Fetsch M. Genetic factors. angio- sarcoma. Juvenile xanthogranuloma. but also. Miettinen Definition Tumours derived from the mesenchymal cells that are similar to those occuring at other sites. malignant peripheral nerve sheath tumour.Mesenchymal tumours J. and rhabdomyosarcoma are primarily paediatric tumours. ICD-O codes Benign Haemangioma variants Lymphangioma variants Neurofibroma Schwannoma (neurilemoma) Granular cell tumour Myointimoma Leiomyoma Glomus tumour Fibrous histiocytoma Juvenile xanthogranuloma Intermediate Biologic Potential Giant cell fibroblastoma Dermatofibrosarcoma protuberans Malignant Kaposi sarcoma Epithelioid haemangioendothelioma Angiosarcoma Leiomyosarcoma Malignant fibrous histiocytoma (including myxofibrosarcoma) Rhabdomyosarcoma Epithelioid sarcoma Synovial sarcoma Clear cell sarcoma Malignant peripheral nerve sheath tumour Peripheral primitive neuroectodermal tumour Ewing sarcoma Extraskeletal osteosarcoma 8834/1 8832/3 9140/3 9133/3 9120/3 8890/3 8830/3 8900/3 8804/3 9040/3 9044/3 9540/3 9364/3 9260/3 9180/3 Fig. 5. 5. and human herpesvirus 8 {101. all of the listed tumours conform to definitions provided in other WHO fascicles (i. B Lymphangioma circumscriptum of the penis. dermatopathology.

and angiosarcoma are usually tumours of mid and late adult life.g. Kaposi sarcoma has a strong predilection for the glans and prepuce. respectively. and leiomyosarcoma is somewhat more common on the shaft and base of the penis. Clinical features Most benign mesenchymal tumours of the penis present as a small. is considered an indicator of AIDS {2}. A The process has immature but well formed vascular channels lined by plump epithelioid endothelial cells. Malignant tumours generally occur at a later age. are more often tender or painful. Rhabdomyosarcomas of the penis are almost always located at the penopubic junction. they may have a multinodular appearance. and neurofibromas and schwannomas. and often. Mesenchymal tumours 293 Table 5. and frequently grow more rapidly. Malignant tumours tend to be poorly demarcated. NOS Haemangioma variants (excluding EH) Lymphangioma (other than LC) Angiosarcoma Malignant fibrous histiocytoma Epithelioid vascular tumours of UMP Unclassified sarcoma Neurofibroma Schwannoma Granular cell tumour Epithelioid haemangioma (EH) Myointimoma Leiomyosarcoma Kaposi sarcoma Number of cases 1 1 1 1 1 2 2 2 2 3 3 3 3 4 5 6 6 7 9 10 14 30 Age range (mean) 49 68 51 1 51 23 – 47 1 – 55 27 25 – 41 28 – 60 26 – 47 (35) 38 – 81 (63) 51 – 86 (74) 35 – 51 (44) 39 – 81 (59) 9 – 58 (26) 20 – 73 (47) 20 – 60 (41) 39 – 75 (50) 2 – 61 (29) 43 – 70 (53) 42 – 91 (65) . Among malignant tumours. plaque. they usually form a solitary nodule. A lymphocytic and eosinophilic inflammatory infiltrate is present. Macroscopy Haemangiomas and lymphangiomas have grossly apparent blood or lymph filled spaces. Superficial vascular tumours may exhibit erythematous or bluish colouration. Tumour type Glomus tumour Leiomyoma Fibrous histiocytoma Giant cell fibroblastoma Epithelioid haemangioendothelioma Angiokeratoma Lymphangioma circumscriptum (LC) Epithelioid sarcoma Fibromyxoma. immunosuppressive/cytotoxic therapy. Neurofibromas have a well marginated. Kaposi sarcoma of the penis diagnosed by a definitive method before the age of 60. third and fourth decades. pink or yellow colouration.30 Epithelioid haemangioma of the penis. poorly marginated. which affect the corpus spongiosum of the glans and coronal regions. which more commonly affect the shaft and base. B Fig. often with a bluish or erythematous appearance. and schwannomas affect a higher percentage of patients in the fifth decade and above. or nodule. are otherwise nonspecific from a gross standpoint. and often. 5. and genetic immunodeficiency syndromes). painless mass. infiltrative. Leiomyomas generally occur in mid adult life.A Fig. slowly enlarging. Lymphangioma circumscriptum often presents as patches of translucent vesicles. malignant fibrous histiocytoma. or plexiform ("bag of worms") appearance and a solid offwhite or myxoid cut surface. 5. certain lymphoproliferative disorders. B This vascular was well demarcated and centered on a small muscular artery (note elastic lamina).29 Lobular capillary haemangioma (pyogenic granuloma) of the penis. Localization Most benign soft tissue tumours of the penis do not exhibit a clear predilection for a specific site except myointimomas. but infrequently. and destructive masses. Leiomyosarcoma. Schwannomas are typically well demarcated masses with white. and in the absence of other disqualifying causes for immunodeficiency (e. Granular cell tumours tend to be poorly circumscribed and often have yellowish colouration and a scirrhous consistency. Kaposi sarcoma presents as a patch.02 Soft tissue tumours of the penis: AFIP data for 116 cases (1970-1999).

dilated. A Note the plexiform/multinodular appearance at low magnification. C The lesional cells have immunoreactivity for calponin. but mitotic activity is generally minimal. Well developed Antoni A areas may exhibit nuclear palisading and contain Verocay bodies. localized intraneural. Myointimoma is a highly distinctive intravascular myointimal proliferation. and it is commonly associated with a lymphocytic and eosinophilic inflammatory infiltrate. and residual neurofilament protein-positive axons. and calponin. Atypia should not be pronounced and mitotic figures should be rare or absent. In contrast with neurofibromas. and melanotic stellate-shaped and spindled cells are present in pigmented neurofibroma. 294 Tumours of the penis . Wagner-Meissner-like bodies are often present in diffuse neurofibroma. Nuclear features vary. A This example was associated with prominent pseudoepitheliomatous hyperplasia of the epidermis. pigmented. and it tends to have minimal reactivity for D33 and DE-R-11 desmin clones. These tumours feature epithelioid or spindled cells with abundant granular eosinophilic cytoplasm. 5. and occasional mitoses are acceptable. growth pattern. This process is usually intimately associated with a small muscular artery. Epithelioid haemangioma (angiolymphoid hyperplasia with eosinophilia) contains immature. 5. often with multinodular or plexiform architecture. diffuse. atypia (often considered degenerative) is a common finding. B The neoplastic cells are strongly immunoreactive for S100 protein.33 Myointimoma of the penis. plexiform. Leiomyomas consist of a proliferation of well developed smooth muscle cells with- A B C Fig. and location. Angiokeratoma and lymphangioma circumscriptum feature superficial. Granular cell tumours are S100 proteinpositive neural neoplasms of Schwann cell derivation. This process commonly has extensive immunoreactivity for αsmooth muscle actin. Additional features commonly encountered in schwannomas include thick-walled vessels and perivascular xanthoma cells. 5. respectively. All of these tumours feature S100 proteinpositive Schwann cells admixed with varying numbers of EMA-positive perineurial cells. B Fig. capillary-sized vessels lined by plump epithelioid (histiocytoid) endothelial cells.32 Granular cell tumour of the penis. that tends to involve the corpus spongiosum. A variety of neurofibroma subtypes are recognized.A Fig. and epithelioid variants. include solitary cutaneous.31 Neurofibroma of the penis. A fibrous connective tissue reaction may be present. muscle-specific actin (HHF-35). and superficial examples may be associated with prominent pseudoepitheliomatous hyperplasia (sometimes mistaken for squamous carcinoma). blood or lymph-filled vessels. but well formed. Histopathology Benign vascular lesions are classified on the basis of vessel type. CD34-positive fibroblasts. Schwannomas (neurilemomas) are well demarcated peripheral nerve sheath tumours that classically exhibit Antoni A (cellular) and Antoni B (loose myxoid) growth patterns. B This unusual process appears to originate from the vascular intima.

g.q11)]. Some sarcomas are generally considered low-grade (e.18) ((p11. a lymphoplasmacytic inflammatory infiltrate.g. dermatofibrosarcoma protuberans [t(17. Early stage (patch/plaque) lesions of Kaposi sarcoma consist of a proliferation of small capillary-sized vessels around pre-existing dermal vessels and adnexae. Angiosarcoma has a broad morphologic spectrum. based primarily on the modified French Federation of Cancer Centers Sarcoma Group system {970}. The protrusion of small proliferating vessels into the lumen of a larger pre-existing vessel (the so-called promontory sign) is also a helpful finding. Note the presence of plump epithelioid tumour cells with eosinophilic cytoplasm. Longitudinal cytoplasmic striations and juxtanuclear vacuoles may be present. At one extreme. endothelial atypia with hyperchromasia. neurilemoma (allelic losses in 22q and/or mutations in the NF2 gene). it may have a spindled appearance reminiscent of fibrosarcoma or an epithelioid appearance resembling carcinoma or melanoma. and at the other. synovial sarcoma [t(X. cell crowding and piling. and a fascicular growth pattern.g. The vessels may contain apoptotic nuclei. Haemosiderin deposition. Factor VIIIr Ag and CD34 help establish the correct diagnosis.22)(q22. we assign a numeric grade. and synovial sarcoma). Genetics Specific cytogenetic or molecular genetic abnormalities have been identified for neurofibroma (allelic losses in 17q and/or mutations in the NF1 gene). and grapelike clusters of intracytoplas- mic hyaline globules. Infiltrative and interanastomosing growth. melanocytic. when present. Hyaline globules are typically abundant by this stage. 5. This diagnosis should be made only after careful examination.22)]. clear cell sarcoma. no mitotic activity. and they may also express CD31. Note the slit-like vascular spaces and presence of grape-like clusters of hyaline globules. mitotic activity.q13) or supernumerary ring chromosome derived from t(17.q12)]. Kaposi sarcoma) or high-grade (e. epithelioid sarcoma. out significant atypia. For the majority of soft tissue sarcomas. epithelial. are helpful clues. Others may be graded in one system but not in another (e.34 A Kaposi sarcoma of the penis (nodular stage).A for human herpesvirus 8 can be helpful in early stage or variant lesions.22) (q13. Later stage (nodular) lesions of Kaposi sarcoma are dominated by spindled cells with fascicular growth and slit-like vascular spaces. peripheral primitive neuMesenchymal tumours 295 B Fig. myogenic or neural differentiation). as leiomyomas appear to be much less common then leiomyosarcomas in this location. clear cell sarcoma [t12. A garland growth pattern is often evident at low magnification. the process may closely resemble a benign haemangioma. Grading The grading of malignant soft tissue tumours is controversial. PCR analysis . and generally. Immunoreactivity is usually detected for αsmooth muscle actin and desmin.g. This diagnosis is restricted to pleomorphic tumours (often with myxoid or collagenous matrix and a storiform growth pattern) that lack morphologic and immunohistochemical evidence for another specific line of differentiation (e. Leiomyosarcomas contain spindled cells with nuclear atypia. rhabdomyosarcoma and peripheral primitive neuroectodermal tumour). B Epithelioid sarcoma of the penis. The lesional cells of Kaposi sarcoma are usually immunoreactive for CD34. These cells often have an "open" chromatin pattern with a small but distinct central nucleolus. Malignant fibrous histiocytoma is a diagnosis of exclusion. and immunoreactivity for CD31.

q14)] {1444}.03 Mesenchymal tumours of the penis in the literature. RT-PCR tests are available for the four fully malignant tumours listed here.2103} {1714.2523} {760} {1331. However.13) (q35.q14) and t(1.1959.q12).1998} {972. paraffin-embedded tissue. t(21. Prognosis Superficial.1173. These tests can often be performed on fresh or formalin-fixed.1136.1983} {1367.811. There is insufficient data to provide site-specific prognostic information for the remainder of the sarcomas listed above. including immune status and the extent of disease. the majority of patients with Kaposi sarcoma die of an unrelated event.1566.2794} {627.22)(q24. benign mesenchymal lesions generally can be expected to have a low recurrence rate. Tumours listed in the intermediate biologic potential category have a high rate of local recurrence.2275} {1043} {2398} {581} {382.2106.2361} {1356.roectodermal tumour/Ewing sarcoma [primarily t(11.789.2300} {333. The outcome for patients with Kaposi sarcoma is dependent on a variety of factors.1671.2248} {1713} {864.761. Table 5.2232.2247} {49} {2312} {581} {2622} {2271} Benign Intermediate Biological Potential Malignant 296 Tumours of the penis .13)(p36. Category Haemangioma variants Lymphangioma variants Neurofibroma Schwannoma (neurilemoma) Granular cell tumour Myointimoma Glomus tumour Juvenile xanthogranuloma Giant cell fibroblastoma Dermatofibrosarcoma protuberans Kaposi sarcoma Epithelioid haemangioendothelioma Angiosarcoma Leiomyosarcoma Malignant fibrous histiocytoma (including myxofibrosarcoma) Rhabdomyosarcoma Epithelioid sarcoma Synovial sarcoma Clear cell sarcoma Malignant peripheral nerve sheath tumour Peripheral primitive neuroectodermal tumour/Ewing sarcoma Extraskeletal osteosarcoma Reference {383. and t(7.1779} {545.q12)]. and alveolar rhabdomyosarcoma [t(2.22)(p22.q12).1987. but only rarely give rise to metastases.1978.22) (q22.1599} {1005.1889. Deep-seated benign lesions have a greater propensity for local recurrence.1305.

1458. priapism {123}. Both nodal and cutaneous Non-HodgkinLymphomas may involve the penis (secondary PL) {1416. 188. Only 22 primary PL have been reported to date {107.1503. Incidence PL are very rare and most are considered to be primary {452}.2908}.2508.1625.2787}. Lymphomas 297 . Prognosis and predictive factors In the few.739.1514.1625} and single cases of anaplastic large cell lymphoma (ALCL) of T-type (CD30+) {1503} and Hodgkin lymphoma have been reported as primary PL {2075}. Marx Definition Primary penile lymphomas (PL) are those that are confined to the penile skin. glans or prepuce {107}.2908}. Clinical features and macroscopy Painless or rarely tender swelling or ulcer of penile shaft. Systemic B symptoms appear to be an exception among primary PL {739}. and corpora cavernosa and spongiosum.739.1503}. Histopathology Several cases of diffuse large B-cell lymphomas (DLBCL) {107. while other cases {2508} including a probable cutaneous penile lymphoma.1036. Synonym Penile lymphoma.1036. 2787.or radiochemotherapy with 42-72 months of follow-up {107.2787}. Precursor lesions and histogenesis (postulated cell of origin) Precursor lesions and the histogenesis of PL are unknown. or associated Peyrone dis- ease {2908} have been reported in PL.123.684. Some PL are cutaneous lymphomas {452. documented primary PL no death occurred after primary chemo.1503} or radiation {2508} alone. Lymphomas of the urethra are counted among urinary tract lymphomas.452. Whether other primary PL occur due to an occult nodal lymphoma (implying systemic chemotherapy) {452} or a penile inflammatory process is unclear {107}.342. Somatic genetics and genetic susceptibility Genetic findings specific to PL have not been reported. scrotal masses {739. subcutis. were apparently cured by surgery {1458.1458}. Recurrences and dissemination were seen in a few penile lymphomas after radiotherapy {1036} or surgery as single modality treatments {684.Lymphomas A.

Secondary tumours of the penis C. 5. Sesterhenn Definition Tumours of the penis that originate from an extra penile neoplasm. 18 bladder. Origin of metastases Reports invariably find prostate and bladder to be the most common primary sites with kidney and colon much less frequent {2905}. Clinical features The presenting symptoms are frequently priapism or severe penile pain {1826}. Any patient with known cancer who develops priapism should be suspected of having metastatic disease. The tumour fills the corpus cavernosum. By 1989 only 225 cases had been reported {2049}. In a series of 60 cases. Other features include increased penile size. Histopathology Tumour deposits may be seen in any part of the penis but the common finding is filling of the vascular spaces of the erectile tissue and the tumour morphology will be typical of that seen in the primary tumour {2202}. Incidence Metastatic carcinoma to penis is rare.K. but the penile skin. Prognosis The prognosis is very poor since this usually occurs in the late stages in patients with known metastatic carcinoma. In another. 21 were prostatic. 14 undetermined primary sites. Tunica albuginea is at the top. 2 kidney.35 Metastatic renal cell carcinoma.A. 3 colon. Mostofi I. 5. 298 Tumours of the penis . Fig. 71% died within 6 months {1826}. Localization The corpus cavernosum is the most common site of metastases. Many other primary sites are occasionally reported. Fig. Davis F. A multinodular growth pattern in the CC is characteristic. ulceration or palpable tumour nodules {2202}. corpus spongiosum and mucosa of glans may be affected {2905}. In one study 95% of patients died within weeks or months of diagnosis.36 Metastatic renal cell carcinoma.J. Cross section of the penis filled with RCC. 1 stomach and 1 pulmonary.

+52 56 27 69 00 / 69 57 Fax. + 349 3416 9700 Fax. +1 410 614 9663 pargani@jhmi.aaltonen@helsinki. Department of Pathology Medical College of Georgia Murphey Building. +33 1 44 73 62 82 liliane. Room 153 The John Hopkins University 1650 Orleans Street Baltimore. +1 410 502 9817 ademarz@jhmi. +1 913 588 7090 Fax. +1 317 274 5346 lcheng@iupui.edu Dr Liang CHENG Pathology & Laboratory Medicine UM 3465 Indiana University Hospital 550. Euclid Avenue Campus Box 8118 St Louis.uu.fi Dr Ferran ALGABA* Department of Pathology Fundacion Puigvert (IUNA) C. Box 626 Rochester. Newtown. +5519 3289 3897 athanase@fcm.ap-hop-paris. +1 212 794 3186 cordon-c@mskcc. North University Boulevard. of Med. + 349 3416 9730 falgaba@fundacio-puigvert.edu Dr Carlos CORDON-CARDO Division of Molecular Pathology Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York. December 14-18.O.Contributors Dr Lauri A. MO 63110-2696 USA Tel.es Dr William C.zk. 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ac. IN 46202-5120 USA Tel. +44 131 5371013 Ken.hospvd.edu Dr Kenneth A.hailemariam@ksli. GEURTS VAN KESSEL Department of Human Genetics 417 University Medical Center Nijmegen P.edu Dr Arndt HARTMANN Institute of Pathology University of Regensburg Franz-Josef-Strauss Allee 11 D-93053 Regensburg GERMANY Tel.kbhamt. +81 3-3437-0388 blueandwhite@earthlink. +44 1 392 402 963 / 914 Fax. Center at Omaha 6001 Dodge Street Omaha. Mitakashi 181-8611 Tokyo JAPAN Tel.keen@rdehc-tr. MO 63110 USA Tel. GRIGNON* Department of Pathology Harper University Hospital Wayne State University 3990. A 128 Indianapolis. +1 212 639 4559 geraldw@mskcc.heitz@pty. +1 317 274 8769 jgrosfel@iupui. +49 221 478 5198 a.se Dr M. 4522 Fax. +41 61 925 26 25 Fax. +1 352 379 4023 iczkoka@pathology.org Dr Charles E. +1 207 871 6268 jonesm@mmc. Chuo-ku 104-0045 Tokyo JAPAN Tel. +1 313 745 8673 dgrignon@med. +1 402 559 6018 sjohanss@unmc.wustl. +31-24-3614107 Fax. of Pathology. 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East Lake Avenue Los Angeles. +31 20 512 2553 Fax.uk 300 Contributors . of Pathology and Laboratory Medicine Maine Medical Center 22. +1 410 955 0115 jepstein@jhmi.nhs. of Pathology Weinberg Bldg. KAPLAN Division of Urology Children’s Specialists of San Diego 7930 Frost Street Suite 407 San Diego. +1 317 274 4966 Fax. and Urologic Pathology University of Nebraska Med.usz. +41 1 255 44 40 philipp. Barnhill Drive Indianapolis.8091 Zürich SWITZERLAND Tel.uni-regensburg. CA 92123-4286 USA Tel. +20 2 3927964 / +20 2 3644720 Dr Jonathan I. North Broadway Baltimore. +41 1 255 25 00 Fax.Grigor@ed. EPSTEIN* Dept. +1 410 955 5043 Fax. +1 314 747 2040 humphrey@path.mil Dr Masakuni FURUSATO Department of Pathology Kyorin University 6-20-2 Skinkawa. +1 314 362 0112 Fax. +1 323 865 0102 jones_p@ccnt. +41 21 314 7207 louis. +49 221 478 3632 Fax. North Wolfe Street Baltimore. Bramhall Street Portland. KEEN Dept.usc. Box 8118 Dept. Apt.W.ch Dr William L.edu Dr George W.go. +1 212 639 5858 Fax. Barnhill Drive. +49 941 944 6600 Fax.gasser@ksli.jp Dr Axel HEIDENREICH Department of Urology University of Cologne Joseph-Stelzmann-Str 9 50931 Köln GERMANY Tel.edu Dr Michael A. JOHANSSON Deptartments of Surgical Pathology. MS Science Bldg. EL-BOLKAINY Lewa Building 2.GeurtsVanKessel@antrg. +41 61 925 20 94 seife. +31-24-3540488 A.egevad@onkpat.org Dr A. +46 8 33 1909 lars. BOX 50 FIN-90029 OYS FINLAND Tel. +1 202 782 9182 fetsch@afip. NY 10021 USA Tel.O.nl Dr David J. rue du Bugnon CH-1011 Lausanne SWITZERLAND Tel.hsc. JONES USC/Norris Comprehensive Cancer Center & Hospital NOR 8302 L University of Southern California 1441.net Dr Thomas GASSER* Urologic Clinics University of Basel Rheinstrasse. +44 1 392 402 915 charlie.de Dr Riitta HERVA Oulu Uviversity Hospital Department of Pathology P. EH4 2XU UNITED KINGDOM Tel. GERALD Department of Pathology Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York.of Histopathology and Cytopathology Royal Devon and Exeter Hospital Barrack Road Exeter.J. +1 317 274 1738 / 7603 Fax. +41 21 314 7216 / 7202 Fax.dk Dr Sonny L. +41 61 925 28 06 thomas. +1 313 745 2520 Fax. Sherif street. +49 941 944 6605 Fax. +1 858 279 8876 gkaplan@chsd.ac. ECCLES Wessex Clinical Genetics Service Princess Anne Hospital Southampton SO16 5YA UNITED KINGDOM Tel.uk Dr Lars EGEVAD* Department of Pathology and Cytology Karolinska Hospital SE 171 16 Stockholm SWEDEN Tel. Cytopathology. Room 2242 The John Hopkins Hospital 401.ufl. EX2 5DW UNITED KINGDOM Tel. +1 410 955 8450 / 7410 Fax. Box 9101 6500 HB Nijmegen THE NETHERLANDS Tel. +1 202 782 2799 / 2790 Fax. FL 32608-1197 USA Tel.edu Dr Grete Krag JACOBSEN* Department of Pathology Gentofte Hospital University of Copenhagen Niels Andersens Vej 65 DK-2900 Hellerup DENMARK Tel.nl Dr Peter A. +358-8-3155362 Fax.ch Professor Ulrike Maria HAMPER Department of Radiology The John Hopkins University School of Medicine 600. +81 3 3248 2463 tdhasega@ncc. S.ch Dr Seife HAILEMARIAM* Cantonal Institute of Pathology Rheinstrasse 37 CH-4410 Liestal SWITZERLAND Tel. 7129) Fax. NE 68198-3135 USA Tel. MD 21287 USA Tel. +44 131 537 1954 Fax. John R Street Detroit. +20 2 3374886 / +20 12 3470693 Fax. of Pathology & Immunology Washington University School of Medicine 660.edu Dr Diana M. Euclid Avenue St Louis.edu Dr Louis GUILLOU Institut Universitaire de Pathologie Université de Lausanne 25. EBLE* Dept. +1 317 278 2018 jeble@iupui. +44 23 8079 8537 Fax +44 23 8079 4346 de1@soton. +46 8 5177 5492 Fax. +81 422-47-5511 (ext.hartmann@klinik. DC 20306-6000 USA Tel.osd.edu Dr John F. Med. +1 402 559 7681 Fax. +41 61 925 21 70 Fax. +49 941 944 6602 arndt. Tsukiji 5-chome.uk Dr Jay L. +1 410 614 9865 / +1 410 955 0231 umhamper@jhu. HEITZ Department of Pathology UniversitätsSpital Zurich Schmelzbergstrasse 12 CH . +45 39 77 36 18 Fax. +49 941 944 6602 ferdinand. +81 3 3547 5201 (ext. +1 352 376 1611 ext.ki.umcn. MI 48201 USA Tel. of Pathology & Laboratory Medicine Indiana University School of Medicine 635.ch Dr Burkhard HELPAP* Chefarzt Institut fur Pathologie Hegau Klinikum Virchowstrasse 10 78207 Singen GERMANY Tel. FETSCH Department of Soft Tissue Pathology Armed Forces Institute of Pathology 14th Street & Alaska Avenue. Klinikum F. 18 11796 Cairo EGYPT Tel.heidenreich@uni-koeln. HUMPHREY* Division of Surgical Pathology.guillou@chuv. Strauss Allee 11 D 93053 Regensburg GERMANY Tel.Dr John N. ICZKOWSKI Dept.hofstaedter@klinik. University of Florida and Veterans Administration Medical Center Room E126 F 1601 SW Archer Road Gainesville.

Tel. +39 071 5964830 Fax. EC1A 7BE UNITED KINGDOM Tel.seoul.uk Dr J.nl Dr Attilio ORAZI Department of Pathology Indiana University School of Medicine Riley Hospital.montironi@popcsi. KGV Building. King’s.org Dr Tim D. +44 20 73789510 henrik.ac. Be 430b Erasmus University Med.B.org Dr W. +49 761 270 3578 / 3401 Fax.knowles@cancer.mil Dr Holger MOCH* Institute for Pathology University of Basel Schönbeinstrasse. LS9 7TF UNITED KINGDOM Tel. S. +1 612 273 1142 maniv001@umn.unian.com Dr Alexander MARX Department of Pathology University of Wuerzburg Josef-Schneider-Strasse 2 97080 Wuerzburg GERMANY Tel. +44 20 7796 0432 c. +44 113 242 9886 margaret.E.ukl.nl Dr Antonio LOPEZ-BELTRAN* Unit of Anatomical Pathology Cordoba University Medical School Avenida Menendez Pidal s/n 14004 Cordoba SPAIN Tel. MCLEOD Urology Services.azr.kiuru@helsinki. MA 02114 USA Tel. MERINO Department of Surgical Pathology Building 10. Scuro 10 37134 Verona ITALY Tel. +41 61 265 31 94 hmoch@uhbs. +49 6221 564634 gyula. +31 10 408 8329 / Fax. +886 2 28757449 ext. Box 63 (Haartmaninkatu 8) FIN-00014 Helsinki FINLAND Tel.moller@kcl. +1 317 630 7913 hmichael@iupui. +1 317 274 7250 Fax.de Dr Manuel NISTAL Department of Morphology Universidad Autonoma de Madrid c/ Arzobispo Morcillo s/n 28029 Madrid SPAIN Tel. Room 2N212 National Cancer Institute 9000.O.tw Dr Margaret A. +31 10 408 8365 looijenga@leph. +358-9-1911 Fax. Washington. +49 931 201 3776 Fax. Holcombe Boulevard Box 0072 Houston. Room 2B47 Bethesda.W. Rm.uni-wuerzburg. King’s College London 1st Floor.org Dr Maria J. +1 202 782 2310 david. TX 77030 USA Tel. +358-9-19125105 E-mail maija. +49 6221 566519 Fax.de Dr David G. +41 1 255 4551 paul.org Dr Virpi LAUNONEN Department of Medical Genetics Biomedicum Helsinki / University of Helsinki P. Marston LINEHAN Urologic Oncology Branch NCI Center for Cancer Research National Institutes of Health Building 10. Rockville Pike Bethesda. N.osd. +1 212 639 6369 Fax. +31 10 40 88450 j.uni-heidelberg. +1 617 726 7474 eoliva@partners. NY 10021 USA Tel.l.edu Dr Esther OLIVA Pathology. Medical School 420 Delaware St.edu Dr Guido MARTIGNONI* Dipartimento di Patologia Sezione Anatomia Patologica Universita di Verona. +44 20 7378 7688 / Fax. +1 301 496 2441 Fax. Kash MOSTOFI Department of Genitourinary Pathology Armed Forces Institute of Pathology 14th and Alaska Avenue. +358-9-19125105 virpi.mcleod@na. 16th Street. +49 761 270 3778 neumann@mm41.es Dr J. / Univ. +1 301 402 0922 Dr Leendert H. DC 20307-5001 USA Tel. +1 301 480 9488 mjmerino@mail. MN 55455 USA Tel. DC 20306-6000 USA (deceased) Dr Hartmut P. +1 713 745 0736 jmedeiro@mdanderson. +34 91 397 5353 Dr Lucien NOCHOMOVITZ Department of Pathology North Shore University Hospital 300 Community Drive Manhasset NY 11030 USA Tel. +39 045 8074846 Fax. of Nephrology and Hypertension Albert-Ludwigs-University Hugstetter Strasse 55 D-79106 Freiburg GERMANY Tel.ch Dr Henrik MØLLER Thames’ Cancer Registry Guy’s.oosterhuis@erasmusmc. +1 202 782 2793 Fax. +1 617 724 8272 Fax. +49 431 597 3444 Fax. DC 20306-6000 USA Tel.H.O.J. Wolter OOSTERHUIS Department of Pathology. Carlos MANIVEL Dept. MD 20892 USA Tel. 213 Fax. +886 2 28757056 ccpan@vghtpe. Box 63 (Haartmaninkatu 8) FIN-00014 Helsinki FINLAND Tel.C. MMC 76 Minneapolis. OLIVER Department of Medical Oncology Saint Bartholomew’s Hospital 1st Fl. LEVIN Department of Pathology Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland. Songpa-gu 138-736 Seoul KOREA Tel. +44 113 206 4913 Fax. IU Medical Center 702 Barhhill Drive Room 0969 Indianapolis. OH 44195-5038 USA Tel.fi Dr Paul KLEIHUES Department of Pathology University Hospital CH-8091 Zurich SWITZERLAND Tel. West Smithfield London. Center Josephine Nefkens Inst. Policlinico G. +1 317 274 0149 aorazi@iupui. +1 212 717 3515 ladanyim@mskcc. +41 61 265 2890 Fax. +1 612 273 5848 Fax.kr Dr Maija KIURU Department of Medical Genetics Biomedicum Helsinki / University of Helsinki P. & St Thomas’ School of Med. NEUMANN Dpt. 40 CH 4003 Basel SWITZERLAND Tel. Jeffrey MEDEIROS Division of Pathology & Laboratory Med. Room Be 200a Erasmus Medical Center Josephine Nefkens Institute PO Box 1738 3000 DR Rotterdam THE NETHERLANDS Tel. IN 46202 USA Tel. +82 2 472 7898 krkim@amc. +34 957 218229 em1lobea@uco. +358-9-19125379 Fax. +1 202 782 9182 miettinen@afip.kovacs@urz.uni-kiel.org.uk Dr Rodolfo MONTIRONI* Institute of Pathological Anatomy & Histopathology University of Ancona School of Med. Warren 2/Rm 251 A Massachusetts General Hospital 55 Fruit Street Boston.launonen@helsinki. IN 46202 USA Tel. +1 516 562-4591 lnochomo@nshs. +39 045 8027136 guidomart@yahoo. +41 1 255 3516 Fax. +31 10 40 88449 Fax. Box 2040 3000 CA Rotterdam THE NETHERLANDS Tel.kleihues@usz. M.mil Dr L.Dr Kyu Rae KIM Department of Pathology University of Ulsan College of Medicine Asan Medical Center 388-1 Pungnap-dong.uni-freiburg.O.uk Dr Gyula KOVACS* Laboratory of Molecular Oncology Department of Urology University of Heidelberg Im Neuenheimer feld 325 D 69120 Heidelberg GERMANY Tel. Sec.ch Dr Howard S. +1 202 782 6408 Fax.edu Dr Markku MIETTINEN Department of Soft Tissue Pathology Armed Forces Institute of Pathology 6825. +82 2 3010 4514 Fax. MD 20892 USA Tel.gov. I-60020 Torrette. NW Washington. KNOWLES Cancer Research UK Clinical Centre St James’ University Hospital Beckett Street Leeds.nih.LE L. +39 071 889985 r. Anderson Cancer Center 1515. N. +49 931 201 3440 / 3505 path062@mail. +34 91 727 7300 / 397 5323 Fax.gov Dr Helen MICHAEL Department of Pathology Indiana University School of Medicine Wishard Memorial Hospital 1001 West 10th Street Indianapolis.amedd.army.fi Dr Ivo LEUSCHNER Department of Pathology University of Kiel Michaelsstrasse 11 D-24105 Kiel GERMANY Tel.de Dr Marc LADANYI Department of Pathology Room S-801 Memorial Sloan-Kettering Cancer Center 1275.de Contributors 301 . 2 Shih-Pai Road 11217 Taipei TAIWAN R. Rotterdam Laboratory for Experimental Patho-Oncology P. +1 516 562-3249 Fax.it Dr F.w.edu Dr Chin-Chen PAN Department of Pathology Veterans General Hospital-Taipei No. Washington. +1 216 445 6967 levinh@ccf.ac. York Avenue New York. LOOIJENGA* Dept. 201. +1 216 444 2843 Fax.crickmore@gmul.W. of Pathology. Rossi P. Ancona ITALY Tel.O. +1 713 794 5446 Fax.D.A. Ward 56 (CPDR) Walter Reed Army Medical Center 6900 Georgia Avenue. +1 301 496 6353 Fax. +34 957 218993 Fax. of Laboratory Medicine & Pathology University of Minnesota. Hosp. +49 431 597 3486 ileuschner@path. Capital House 42 Weston Street London SE1 3QD UNITED KINGDOM Tel. +44 20 7601 8522 Fax. +1 317 630 7208 Fax.

SOBIN Dept. of Nuclear Medicine & Diagnostic Imaging Graduate School of Medicine Kyoto University 54 Shogoin Kawahara-cho Kyoto 606-8507 JAPAN Tel. +1 773 880 4306 Fax. Côte du Palais Québec. Michigan Avenue N.edu Dr Jerzy E.osd. +81 75 771 9709 ktogashi@kuhp. Constance PARKINSON* UCL Hospitals Trust & Institute of Urology University College London Rockefeller Building University Street London.ca Dr Kaori TOGASHI Dept. +41 61 265 3152 Fax.seoul.mil Dr David SIDRANSKY Dept. Urologic Oncology Johns Hopkins Bayview Medical Center Brady Urological Institute.sg Dr Bernard TÊTU Service de Pathologie CHUQ. +1 410 955 1039 Fax. of Pathology and Pediatrics. VA 23502 USA Tel. Pathology. +1 202 782 2880 Fax.fr Dr M.kyoto-u. TX 77030 USA Tel.de Dr Mark Philip SCHOENBERG Brady Urological Institute Johns Hopkins Hospital 600 N Wolfe St. +1 215 923 1969 Dr Pheroze TAMBOLI Department of Pathology M.edu Dr Bernd J. Urology & Cellular & Molecular Med. Room 3082 Vancouver (BC) V5Z 4H4 CANADA Tel.edu Dr Isabell A.ch Dr Paul F. West Mississauga (Ontario) CANADA Tel. +41 61 265 2966 Guido.ca Dr Stephan STÖRKEL Institute of Pathology University of Witten / Herdecke Helios-Klinikum Wuppertal Heusnerstrasse.edu Dr Ronald SIMON Institut für Pathologie Universität Basel Schönbeinstrasse 40 4003 Basel SWITZERLAND Tel. +41 61 265 2966 ronald_simon_de@yahoo.W. +1 604 875 2936 Fax. +1 418 691 5226 bernard. +61 07 33778666 Fax. Pavlovich Assistant Professor of Urology Director.ca Dr John R. York Avenue New York. 40 42283 Wuppertal GERMANY Tel. SCHMITZ-DRAGER Department of Urology Euromed-Clinic Europa-Allee 1 D-90763 Fürth GERMANY Tel. +1 410 502 5153 / Fax. SORENSEN Depts. +1 212 639 8225 Fax. SCHELLHAMMER Department of Urology Eastern Virginia Graduate School of Medicine 6333 Center Drive Elizabeth Building #1 Norfolk. +44 20 7679 6033 Fax. +1 202 782 2756 Fax. +1 202 884 4739 hrushton@cnmc. G1R 2J6 CANADA Tel.es dep402@uah. IL 60614 USA Tel. A 203 Chicago.osd. WC1E 6JJ UNITED KINGDOM Tel. Eglinton Avenue.kr Professor Mark A. MD 21224 USA Tel.helios-kliniken.org Dr Paola PISANI Unit of Descriptive Epidemiology Office 519 Intl. +1 313 745 9299 wsakr@dmc. Oncology. Anderson Cancer Center 1515.mil Dr Poul H. Max PARKIN Unit of Descriptive Epidemiology Intl. DC 20306-6000 USA Tel. The Johns Hopkins University School of Medicine 818 Ross Research Bldg. +1 305 5966525 Fax.paniagua@uah. +65 6222 6826 gpttph@sgh. QLD 4068 AUSTRALIA Tel. +1 202 884 5550 / 5042 Fax. Holcombe Boulevard Box 0085 Houston.uk Dr Christian P.mil TYREE@afip. RO Department of Pathology Asan Medical Center Ulsan University School of Medicine #3881 Pungnap-dong. of Pathology Sullivan Nicolaides Pathology 134.de Dr Leslie H. +1 202 782 3056 Sesterhe@afip. Whitmore Street Taringa. +49 911 971 4532 bsd@euromed. +1 305 598 5986 AndrewR@bhssf. BC Research Institute for Children's & Women's Health 950 West 28th Avenue.amc. +65 6321 4900 Fax. +1 206 598 4928 / 3803 ltrue@u.org Dr Puay H. +1 410-550-3506 / Fax. +1 757 627 3211 schellpf@evms.org Dr Victor E. Kendall Drive Miami. Cours Albert Thomas 69008 Lyon FRANCE Tel. +1 418 691-5233 Fax. 720 Rutland Avenue Baltimore. Cours Albert Thomas 69008 Lyon FRANCE Tel. SRIGLEY* Laboratory Medicine The Credit Valley Hospital 2200. John R. WA 98195 USA Tel. + 34 91 885 47 99 ricardo.org Dr Wael A. Head & Neck Surgery. +49 911 971 4531 Fax.org Dr H.Dr Ricardo PANIAGUA Department of Cell Biology and Genetics University of Alcala 28871 Alcala de Henares. Songpa-gu 138-736 Seoul KOREA Tel.tetu@crhdq. Marshall Street Little Rock. +81 75 751 3760 Fax. +1 905 813 2696 Fax. +33 4 72 73 86 50 pisani@iarc. +1 604 875 3417 psor@interchange. +33 4 72 73 85 22 Fax. REUTER Department of Pathology Memorial Sloan Kettering Cancer Center 1275.es Dr David M. Outram Road 169608 Singapore SINGAPORE Tel. +1 501 320 1307 Fax. Cours Albert Thomas 69008 Lyon FRANCE Tel.com hema_samaratunga@snp. SESTERHENN* Department of Genitourinary Pathology Armed Forces Institute of Pathology 14th and Alaska Avenue.au Dr Guido SAUTER* Institute for Pathology University of Basel Schönbeinstrasse 40 4003 Basel SWITZERLAND Tel. PARHAM Department of Pathology Arkansas Children’s Hospital 800. Ste 500-3W Washington. Agency for Research on Cancer (IARC) World Health Organization (WHO) 150. +1 617 278 6950 marubin@partners. +1 713 745 3740 ptamboli@mdanderson. +1 410 955 0833 mschoenberg@jhmi. PERLMAN Department of Pathology Children’s Memorial Hospital 2373 Lincoln N.fr Dr Andrew A. L’Hôtel-Dieu de Québec 11. +1 757 457 5175 / 5170 Fax. NY 10021 USA Tel. +1 773 880 3858 eperlman@childrensmemorial. RENSHAW Baptist Hospital Department of Pathology 8900 N.org Dr Jae Y.ac. DC 20306 USA Tel.de Dr Aleksander TALERMAN Department of Pathology Thomas Jefferson University Hospital Main Building 132 South 10th Street.edu Dr Elizabeth J. +1 713 794 5445 Fax. TAN Department of Pathology Singapore General Hospital 1.ulaval. +61 07 33783089 / 33778724 hemamali@medihesa. +44 20 7387 3674 rmkdhmp@ucl.washington. +34 1 885 47 51 Fax. MD 21205-2196 USA Tel. +33 4 72 73 86 50 tyczynski@iarc.D. A-345 4940 Eastern Avenue Baltimore.jp Dr Lawrence TRUE Department of Pathology University of Washington Medical Center 1959. +1 410 614 1411 dsidrans@jhmi. Madrid SPAIN Tel. MD 21287-2101 USA Tel. +1 617 525 6747 Fax. PA 19107-5244 USA Tel. +1 313 745 2525 Fax. of Hepatic & Gastrointestinal Pathology Armed Forces Institute of Pathology 14th Street and Alaska Avenue Washington.edu Dr D. DC 20010-2916 USA Tel. TYCZYNSKI Unit of Descriptive Epidemiology Office 518 Intl.Sauter@unibas. +1 501 320 3912 parhamdavidm@uams. +1 212 717 3203 reuterv@mskcc. +41 61 265 2889 / 2525 Fax. +1 206 598 6400 / +1 206 548 4027 Fax. Marburg 150 Baltimore.fr 302 Source of charts and photographs .com. Agency for Research on Cancer (IARC) World Health Organization (WHO) 150. +82 2 3010 4550 Fax. Hospital Drive. +33 4 72 73 86 50 parkin@iarc. +1 905 813 4132 jsrigley@cvh. +1 202 782 9020 sobin@afip. +82 2 472 7898 jaero@www.ubc. 2088 Washington. NE Pacific Street Seattle. MI 48201 USA Tel.ac. AR 72202-3591 USA Tel. +33 4 72 73 84 82 Fax. +49 202 896 2850 Fax. Agency for Research on Cancer (IARC) World Health Organization (WHO) 150. Gil RUSHTON Department of Urology Children’s National Medical Center 111.com. RUBIN* Department of Urologic Pathology Brigham and Women’s Hospital Harvard Medical School 75 Francis Street Boston. B. +49 202 896 2739 sstoerkel@wuppertal.org Dr Hemamali SAMARATUNGA Dept. +1 215 955 2433 Fax. of Otolaryngology. MA 02115 USA Tel. Street Detroit. NW Rm. SAKR* Department of Pathology Harper Hospital 3990. +1 410-550-3341 cpavlov2@jhmi.on. Room 285Q Philadelphia.osd. FL 33176 USA Tel. +33 4 72 73 84 97 Fax.

+1 713 394 6475 Fax. +46 8 5177 5371 Fax.berg-de. IN 46202-5280 USA Tel. National Cancer Institute Frederick Cancer Research & Dev. University Boulevard Indianapolis. Room 3465 Indiana University Hospital 550.ruiter@medgen.se Dr Thomas WHEELER Department of Pathology Room M227 The Methodist Hospital 6565 Fannin Street.nl Dr Theo H. +46 8 714 9888 / +46 8 08 517 77851 Geo. VAN DER KWAST Department of Pathology Josephine Nefkens Institute Erasmus MC Postbox 1738 3000 DR Rotterdam THE NETHERLANDS Tel. +31 50 3632457 e.osd.nl Dr Annick VIEILLEFOND* Service d’Anatomie & Cytologie Pathologiques Hôpital COCHIN Cochin-St Vincent de Paul-Laroche 27.edu Dr Eva VAN DEN BERG Department of Clinical Genetics Academic Hospital Groningen Ant. +1 202 782 0768 woodwardp@afip. DC 20306-6000 USA Tel.van. Room 12-68 Frederick.vieillefond@cch.Dr Thomas M.mil Dr Ximing J.edu Dr Paula J. IL 60611 USA Tel.gov Source of charts and photographs 303 . +1 713 793 1603 twheeler@bcm.azg. MD 21702 USA Tel. +31 50 3632938 / 3632942 Fax. Center Building 560. TX 77030 USA Tel. MS 205 Houston. +1 312 926-3127 xyang@northwestern. YANG Department of Pathology.vanderkwast@erasmusmc. +1 301 846 1557 Fax. WOODWARD Department of Genitourinary Radiology Armed Forces Institute of Pathology 6825 16th Street NW Washington. +1 312 926-0931 Fax. +33 1 58 41 14 80 annick.tmc. +31 10 4087924 Fax. +1 202 782 2161 Fax.edu Dr Berton ZBAR Laboratory of Immunology. +1 317 274 5346 tulbrigh@iupui. rue du Faubourg Saint Jacques 75679 Paris Cedex 14 FRANCE Tel. +33 1 58 41 14 65 Fax. Feinberg School of Med. 251 E Huron Street Chicago.von. ULBRIGHT* Department of Pathology and Laboratory Medicine.ki. Feinberg 7-334 Northwestern Memorial Hospital Northwestern Univ. +1 317 274 5786 Fax.ap-hop-paris. N. +31 10 4088450 t. +1 301 846 6145 zbarb@mail.Krogh@ood.ncifcrf..fr Dr Geo VON KROGH Department of Medicine Unit of Dermatology and Venereology B:3 Karolinska Hospital /Karolinska Sjukhuset Hudkliniken B2:01 171 76 Stockholm SWEDEN Tel. Deusinglaan 4 NL-9713 AW Groningen THE NETHERLANDS Tel.den.

11A-01.76-01.75A.I.45-01. Delahunt Dr A. Cohen.58A 01. Argani Dr H. Parkinson Dr M. Bonsib Dr J.90C 01. Heitz Dr C. Algaba Dr W. Srigley Dr P.J. Heitz Dr B.B 01.25C 01.104 01. Delahunt Dr J.I.J. Martignoni Dr S.A. Cheville Dr A.I.90-02.11A 02.09 01.J. Lopez-Beltran Dr M.95B 01. Bonsib Dr B. Argani Dr E.04D 02.C.61B 02. Dr G.48 02.19 01.113A 01.B 02.B. Algaba Dr A. Vieillefond Dr R. Lopez-Beltran Dr F.132 Dr A. Dr H. van den Berg Dr S. Lopez-Beltran Dr F.S.M.I.12A 01.M.92-02.G.25A 01. Algaba Dr G.M.99 02.B. Sesterhenn Dr F.79D 02.114B 01. Pisani) Dr P. U. Algaba Dr I.118B 01.19B 02.12B 02. Lopez-Beltran Dr A.56B-02.N.B 01. Lopez-Beltran Dr M.122 01.44C 01. Srigley Dr C. Delahunt Dr P.71C 02.A.39-01.86 02.11B 02.02 01. Tyczynski) Dr T.01 01.I. Lopez-Beltran Dr C. Aaltonen Dr M. 01.B.I.123-01.L. University of Michigan Medical School..23-02.04A 02. Laboratoire d'Anatomie Pathologique.28 02.93 01. Sesterhenn Dr C.32A 01. Istituto di Ematologia e Oncologia Medica.26A. Davis Dr A. Eble Dr P.83-02.80A.N. Orsola. Cheville Dr H.54 02.N.B 02.C 01.M.45B 02. Epstein Dr A.A.20 01.39 02. Delahunt Dr S. Amin Dr I. Vieillefond Dr G. Eble Dr S.105A-01.N. Busch Dr V.67 01.29C 02. Bonsib Dr B. Perlman Dr J.60A.74-02.N. Busch Dr I. Martignoni Dr S.36 02. Ann Arbor MI. Shah. Ann Arbor MI.06A. Vieillefond Dr R.53 01. Pisani IARC (Dr P.85B 01. Shah.91A.N. Sesterhenn Dr M.40 02.01-02.12B 01.S.19C 02.29A.59A 01. El-Bolkainy Dr M. Tyczynski) Dr T.16A 02.86 01.09B 02.G.117-01. Algaba Dr H.37B 02.34B 01. Moch Dr E. Lopez-Beltran Dr F. Paris.116B 01. Shah.47A.70A. Argani Dr P.18B-02. Bruneval. Epstein Dr I.72 02.91 02. Bonsib Dr B.Ro Dr L. Pathology & Urology. Sauter Dr A.112 01. Bonsib Dr R. Lopez-Beltran Dr F.88 02.32B-01.52-02.18A 01. Algaba Dr J.92 01.42-01.B 02. of Pathology & Urology.32 02.14A. Lopez-Beltran Dr F.109 01. Algaba Dr J.113B 01.I. Davis Dr Ph. Delahunt Dr H. Moch Dr J.127A 01. Algaba Dr A. Hartmann Dr M.30 02.34A 01. Ayala Dr A.101B 01. Eble Dr J. Dept.U.28 01. Sauter Dr A. University of Western Australia.61-01.58B-01. Germany Dr T.B.04B.B 02. University of Michigan Medical School.97A-02. Ann Arbor MI.30 01. Nedland.74 01.J.17C 02.88B 01. Algaba Dr M.J. University of Michigan Medical School. U. Merino Dr D. Martignoni Dr F.J.16B-02.21-01. Zaak. Amin 304 Source of charts and photographs .37A.34A 02.49 02.E. Vieillefond Dr A.S. Delahunt Dr P.Y. Dr J.67-02. Lopez-Beltran Dr F.J.116A 01.M. Requests for permission to reproduce figures or charts should be directed to the respective contributor. Lopez-Beltran Dr I.18B IARC (Dr P.63B 02.B.127B 01.72 01. Helpap Dr J. Kovacs Dr C.95A 01.B 02. Cheville Dr M. Keen Dr A. Linehan/Dr B.I.85A 01.B 01.B 02. U. Urologische Klinik und Poliklinik. Ladanyi Dr J.17 01.R.75 02.R. Davis Dr P.29A 01.38A 02. Moch Dr S. Vieillefond Dr P. Gasser Dr A.121-01. Amin Dr J.78A-01. Eble Dr R.70C-02.55 01. of Pathology & Urology.69A.N. Sauter Dr C. Argani Dr C.N.48 01. Moch Dr A.S. Ayala Dr A.J.33 01.35 02.106B 01. Moch Dr B.13A-C 02.G.I.54A. Busch Dr G. Klinikum Großhadern der LMU München.110-01. of Pathology & Urology. Epstein Dr F.B. Shah.27B 01. Reuter Dr C.66 02.Ro Dr P.131-01. Argani Dr R.35 01.129 01.50A-01. Algaba Dr G.68B 02. Hopital Européen G.C 02.37A 02.34B-02.77B 01.62A-02. Delahunt Dr J.E. Lopez-Beltran Dr I.45A 02.J.A. Eble 01. Perlman Dr P. Merino Dr G. Dept. El-Bolkainy Dr A.U.81 02. Sesterhenn Dr C.31B 01. Lopez-Beltran Dr M.66B 01. Helpap Dr A.J. U. Lopez-Beltran Dr M.03A-C 02.15 01.64A-02. Delahunt Dr S.73-01. Argani Dr B.07 01.119 01. Moch Dr B.E.46A 02.20B 02. Ann Arbor MI.125B 01.18A 02. Algaba Dr J.115 Dr H.120A-C 01.C.17D 02. Dr C. Sesterhenn Dr A.111C 01. Epstein Dr A. School. For addresses see Contributors List.B 01.B IARC (Dr J. Pompidou.36 01.95C 01. Eccles Dr M. Parkinson Dr A.87A-01.S.31B 02. Moch Dr J. University of Michigan Medical School.B 01.59B 02.A. Lopez-Beltran Dr F.44A.13A-C 01.N.N.E.A.03 01. Lopez-Beltran Dr B.10A.Source of charts and photographs 1.60 02.96 02. of Pathology & Urology. Bologna.108B 01. Algaba Dr A. University of Michigan Med.B 01. Algaba Dr B.M.81 01. Grosfeld Dr E.41A-C 02. Shah.96A-01. Ann Arbor MI.53 02.88A 01.A.N. Orazi Dr S. Bonsib Dr J.27A 01. Lopez-Beltran Dr J.25B 01. Dept. Kovacs Dr P.M. Vieillefond Dr F. Merino Dr L.B 01.12A 02.J.130A-C 01.22 01. München.A.82 02. University of Michigan Medical School. Argani Dr B. Sesterhenn Dr A.68A-01. Lopez-Beltran Dr F.85B 02.20A 02.50 02. Delahunt Dr J.B. Argani/Dr M. Têtu Dr H.128 01. 01.M. 02. Dr J. Epstein Dr A.102-01. Eble Dr A.B. Cheville Dr J. Bégin Dr L.42 02.S. Amin Dr A.61A 02.114A 01.87A-D 02.55A-02. Zbar Dr M. France Dr S. Busch Dr M.38 01.84B 01. Moch Dr P.89-01.B 02.43 02. Hasegawa Dr S. Busch Dr I.31A 01.A. Delahunt Dr H. Pileri.108A 01.14A. Argani Dr J. Dept.M. Bonsib Dr B. Urological Research Center. Policlinico S.10A.N.89A. Delahunt Dr S. Guillou Dr A.04-01.M. Pisani) Dr M.56A 01.15B 02.07A-02.49 01.59B 01.B 02. Bonsib Dr H. Algaba Dr Ph. Sauter Dr M. U. Vieillefond Dr C.21A-D 02. Eble Dr P.57 01.B 01. Moch Dr R.C.126A-C 01.73 02.B 02. Epstein Dr A.05 01. Kovacs Dr J. U. Busch Dr G. Davis Dr H. El-Bolkainy Dr A. Parkinson Dr J. Epstein Dr F. Gasser Dr A. Gasser Dr A. Hartmann Dr R. Ann Arbor MI.A.08 01. Hartmann/Dr D. Dept.51 02.22 02.56B. Shah.16A-C 01.06A.52C The copyright remains with the authors. Universitá di Bologna.M.J.B 01. Sesterhenn 02. Moch Dr J. of Pathology & Urology. Lopez-Beltran Dr J. Geurts van Kessel Dr S. Kleihues Dr F. Merino Dr A.107 01.B 01. Vieillefond Dr H.46B 02.A.82-01.A.15A 02. Lopez-Beltran Dr R.A. Moch 01.A.08B 02. Argani Dr B.29B 01.B. Gasser Dr M.27 02. Simon Dr G. Eble Dr T.Y. Australia/Dr B. Epstein IARC (Dr J.19A 02.N.09A 02.02 02. Bonsib Dr G. Algaba Dr A.77 02.R. El-Bolkainy Dr T.24A. El-Bolkainy Dr A.76 02. Argani Dr J.56A 02. Dept.05 02. Bonsib Dr J.65 02.78-02.95 02.94 01.38B 02.100 Dr C. El-Bolkainy Dr A. Italy 2.31A 02. Epstein Dr B. Bonsib Dr P.M.33 02. Dr F. Davis Dr G.23 01.B. Ayala Dr A.N.M.41C 01.

A.08 03.A. of Pathology & Urology.K.A.C.59A.34A-C 03.I.59 03.48B-04.22B. Woodward Dr M. Helpap Dr M. Sakr Dr A. Jacobsen Dr T.85A-04.90 04.B 04. Davis Dr I.J. Epstein Dr P.32B-04. Sesterhenn Dr T. Ulbright Dr I.I.M.S.A.19B 05.I.86 04.96A-D 04.C 04.C.C.A. Egevad Dr J.09 04.21B 03.A.B. True Dr I. Amin/Dr J. Jacobsen Dr M. Sesterhenn Dr J.88A 03. Chinnaiyan.M. Egevad Dr J. Srigley Dr I. Humphrey Dr J.40A 03.H.B 04.I. Ulbright Dr M.46A-04.05A-03. Ferlay) Dr M. Humphrey Dr J.05A 05. Woodward Dr M.01 03.A.K.C.64A.73A 04.M. Parkinson Dr M.K. Sesterhenn Dr T.16 03. Humphrey Dr J.118-04.L.107 04.120-04.119B 04. Ayala Dr J.A. Bonsib Dr A.89 03. Egevad Dr J.88A. Humphrey Dr D.A. Looijenga Dr M.J.47-03.J.54-04.A. Dept.26B 05.M.B 03.M.K.29C 04.74A 04.51C 04.13A 04.108B 04.76A 03.A.A.I.I. Parkinson Dr I.11A 05.B 03.M.22A 03. Epstein Dr P.31B 03. Epstein Dr P.A.04B 03.C. Dept. Dr T.A.M. Sesterhenn Dr L. U.B 04.22B-03.10A-C 03. Cubilla Dr S.M. Egevad Dr J. Grignon Dr I. Ulbright Dr I.60B 04. Rubin Dr A. Sesterhenn Dr P. Rubin Dr M. Jacobsen Dr I. Epstein Dr P.109-04.B 04.48 03.M. Sesterhenn Dr L.105A.C.67D-04.33A 03.93C.47B 04. Miettinen Dr P.C.F 04.C 05.C.M. Dr J. Epstein Dr F.50 04.28A 03. Sesterhenn Dr G.103-04.M.K.B 05. Ulbright Dr M.19A 04.44B 04.43D 04.75 04.A. Sesterhenn Dr T.60A 04.M.A.33B 03.A.I.114A.C. Parkinson Dr T.72C 03. 05.I.K. Egevad Dr J.20A-05.3.44A-03.65A 03. Davis 5. Ulbright Dr I.A.65B 04.41 03.L.43A.I. Sesterhenn Dr J.A. Sesterhenn Dr T. Grignon Dr J.63A. Epstein Dr D.I. Humphrey Dr J. Ulbright Dr G.C.I. Sesterhenn Dr T.10A.73 03.72B 04.A.B. Parkinson Dr C. Epstein 4. Sesterhenn Dr T.J.J. Parkinson Dr M.35 04. Shah.64A.B 04. Epstein Dr L.A.30A 03.68 04.56-04.123B Dr T. Miettinen Dr M. Parkinson Dr I. Epstein Dr L. Egevad Dr J. Rubin Dr A. Manivel Dr P.A.J. Woodward Dr M. Egevad Dr J.L. Rubin Dr W.M.76-04.72B 03.61 04.B 04.I. Jacobsen Dr I.B 04.29A. Jacobsen Dr I. University of Michigan Medical School.B 04.M.64C 04.M.I.14A 04.A. Cubilla Dr M. Jacobsen Dr T. of Urologic Pathology.A.B 04. Parkinson Dr D. Miettinen Dr M.12A 05. Jacobsen Dr I.A.B 04.B.13B 04.102 04.58B 04.B 03.J.K. Boston MA. Ulbright Dr I.J.37B 03.35A-03.K. 03.26A 03.122A-04. Hirsch. Grignon Dr J.A.14-03.25 04. Jacobsen Dr I. Brigham and Women’s Hospital.78 04.M.18A-04. Sesterhenn Dr P. Epstein Dr P.121 04.12B.15 04.27A. Ulbright Dr I.32A 03.92B 04.R.77C 03. Sesterhenn Dr H. Vieillefond Dr I.M.A.G.27-05.A. Jacobsen Dr T.28B Dr D.B 04. Sesterhenn Dr T.I.M.57A-03.A.58A 04. Cubilla Dr M.A. U. Epstein Dr L.21 05.57A 04. Cubilla IARC (Dr J. Ulbright Dr G. of Pathology & Urology.C. Ulbright Dr I.04A 03.A.12 04.02 03.77B 03.M.82A-04.M. Sesterhenn Dr L.90 03. 04.46A.J.B 04.30 04.87A.91 Dr G. Ulbright Dr I. Parkinson Dr M.R.110 04. Sakr Dr J.39A 04.48A 04.A.14B 04. Humphrey Dr J.24B 03.C. Fetsch Dr C.03-04.K.J.24 04.D 04.B 03.93A.I.J. Rubin Dr A. Ulbright Dr G.11B. Algaba 03. University of Michigan Medical School.C.10B 05. Egevad Dr J.75A-03.11B-05.A. Sesterhenn Dr T.66B 03.97 04.02 05.A. Woodward Dr M.S. Ulbright Dr G.B 03.A.K.29 03. Humphrey Dr I. Ulbright Dr M. Parkin WHO/NCHS IARC (Dr D. Epstein Dr R.M.01 04. Jacobsen Dr M. Dept.98-04.A.42 03.I. Woodward Dr F.03 03.51B 04.84A 04.32A 04.A. Nochomovitz Dr I.C.J.36 04. Algaba Dr M.B 03. Epstein Dr L.J.18-03.A. Sakr Dr T.A.A. U. Gerald Dr M.43A. Epstein Dr L. Rubin Dr M.73B-04. Ulbright Dr G.30B-03. Sesterhenn Dr G. Sesterhenn Dr T. Sesterhenn Dr M. Epstein Dr I.B. Parkinson Dr I.12A.02 04.I.25-05.I. Amin/Dr J. Ferlay) Dr L.I.03 05.84B 04.A.20A 04. Ulbright Dr I.55 04. Ulbright Dr R.70 04.S. Dept. Epstein Dr L.A.I.67A-C 04. Miettinen Dr P.62A. Parkinson Dr G.39B-04.16A.M.31A 03.66 04.101-04.93E.50 04.05B-05.38A. Ulbright Dr I. Ulbright Dr G.49 03.I. Parkinson Dr T. Parkinson Dr I. Woodward Dr M.62A 03.I.34B-04. Ann Arbor MI.K. Davis Dr J.52A-04.45B 03. Parkinson Dr I.32B 03.76B-03. Møller IARC (Dr J.13A.C.88B 03. Sesterhenn Dr W.66A 03. Woodward Dr M.94A.45 04.22A 04.A.M. Woodward Dr I. Sesterhenn Dr M. Humphrey Dr J.60-03.L. Ulbright Dr G.17A.91-03. Nochomovitz Dr P. Cubilla Dr G.B 04.I. Epstein Dr M. Epstein Dr L.A.B 04. Sesterhenn Dr J. Ulbright Dr I. of Pathology & Urology. Epstein Dr B.49D 04.19B 04. Michael Dr P.K.A.44A 04.B 03.C. Egevad Dr P.67 03.23 04.117 04.45A 03.B 04.95A. Sesterhenn Dr L. Epstein Dr M.M. Parkinson Dr G.78 03.F. Epstein Dr L. Epstein Dr L.35-05. Ann Arbor MI.17B 03.26B-03. Parkinson Dr T.51-03.K. Cubilla Dr A. Epstein Dr J.106-04. Ulbright Dr A.A.J. Woodward Dr T.55 03.22D 04. Ann Arbor MI.J.92A 04.43C 04.A.115 04.I.B 04. Ulbright Dr I.57C.116 04.25A-C 03./Dr M.J. Dr J.M.112 04.C.89-04.B 04.20B-04. Parkinson Dr I. Woodward Dr T.D 04. Epstein Dr J.42A. Sesterhenn 03.100B 04. Sesterhenn Dr T.S.01 05.24A 03. Epstein Dr M.A. Ulbright Dr G.79A-03.A. University of Michigan Medical School.A.A.A. Shah. Humphrey Dr J.11A. Jacobsen Dr T.A.B 04.31-04.69A 04.J. Sesterhenn Dr C. Sesterhenn Dr M.61A 03.111 04. Egevad Dr P.47A 04.L.69B 04.65A. Srigley Dr P.M. Rubin Dr P.04A.81A.80 04. Jacobsen Dr T.72A 04.113 04.57B 04.38A Dr H. Sesterhenn Dr M. Parkin) Dr J.B 03.A.39B 03.A. Parkinson 04.C. Sesterhenn Dr P.28 04.56 03. Sesterhenn Dr C.A.77B 04.I.A. Rubin Dr W.09 03.74A. Parkinson Dr I. Epstein Dr L.39A 03.I.104B 04.53B 04. Davis Source of charts and photographs 305 .26 04.37B-04. Sesterhenn Dr T.B 03. Woodward Dr B. True Dr P.68A-03.34B 05. Wheeler Dr J. Epstein Dr P.M.M.L.108A 04.63A.24 05.11A 04.41 04.79 04. Sesterhenn Dr G. U.33B 04.22-05.I.C 04.37A 04. Epstein Dr L.A.L. von Krogh Dr A. Davis Dr I.62B 04. Sesterhenn Dr P.B 03.I.40B 03.K.96B Dr J.17A 03.51A 04. Jacobsen Dr T. Delahunt Dr C.A.61B 03.I. Parkinson Dr I.36 Dr A. Jacobsen Dr I.13-05.J.C.J. Epstein Dr W.I. Epstein Dr M.74B 04.34A 04. Egevad Dr J.C.38B 04.J.77A 03.71 04.B 04. Sesterhenn Dr J.

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